Processes for preparing a diazabicyclooctane compound

ABSTRACT

wherein in the formula (IV-c), OBn represents benzyloxy, and (b) carrying out an intramolecular urea formation reaction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional application of U.S. application Ser.No. 15/973,861, filed May 8, 2018, which is a Divisional application ofU.S. application Ser. No. 15/583,238, filed May 1, 2017 (now U.S. Pat.No. 10,023,573), which is a Divisional application of U.S. applicationSer. No. 14/872,988, filed Oct. 1, 2015 (now U.S. Pat. No. 9,708,320),which is a Divisional application of U.S. application Ser. No.14/404,288, filed Nov. 26, 2014 (now U.S. Pat. No. 9,181,250), which isa U.S. National Stage application of International Application No.PCT/JP2013/064971, filed May 30, 2013, which claims priority of JapaneseApplication No. 2012-122603, filed May 30, 2012, the entire contents ofall of which are incorporated by reference herein.

TECHNICAL FIELD

The present invention relates to a novel diazabicyclooctane derivativerepresented by the formula (I), a pharmaceutically acceptable saltthereof or a solvate thereof. The present invention also relates to aprocess for preparing the same, and a use thereof as a β-lactamaseinhibitor for the treatment of bacterial infection. The presentinvention further relates to a pharmaceutical composition and a methodof treating bacterial infection using the compound of the presentinvention.

BACKGROUND ART

Penicillins and cephalosporins are β-lactam antibiotics which are mostwidely and frequently used in the clinic. However, the acquisition ofresistance to β-lactam antibiotics by various pathogens severely has hada damaging effect on maintaining the effective treatment of bacterialinfections. The most significant known mechanism related to theacquisition of bacterial resistance is the production of class A, C, andD β-lactamases having a serine residue at the active center. Theseenzymes decompose the β-lactam antibiotic, resulting in the loss of theantimicrobial activities. Class A β-lactamases preferentially hydrolyzepenicillins while class C β-lactamases have a substrate profile favoringcephalosporins. As commercially available β-lactamase inhibitors,clavulanic acid, sulbactam, and tazobactam are known, and theseinhibitors are effective mainly against class A β-lactamase producingbacteria, and used as a mixture with a penicillin antibiotic. However,250 types or more of β-lactamases have been reported to date, and amongthem, in addition to the expansion of class C β-lactamases as well asextended-spectrum β-lactamase (ESBL) belonging to class A and Dβ-lactamases, further resistant bacteria which produce class A KPC-2β-lactamase decomposing even carbapenem as a last resort for β-lactamantibiotic is being considered as a problem. The development of a novelinhibitor is strongly demanded as the commercially available inhibitorsare ineffective against these β-lactamases.

Also, in recent years, infectious diseases caused by the above-mentionedresistant bacteria as pathogenic bacteria are found not only in severeinfectious disease but also occasionally in community-acquiredinfectious disease, so that the development of a novel inhibitor whichcan be used in combination with the drug of first alternative (forexample, penicillins or cephalosporins) in a city is strongly demanded.However, although there are a report of potential inhibitors and areport for treating severe infectious disease, there are only a fewcandidates under development.

In recent years, U.S. Pat. No. 7,112,592 (Patent document 1), U.S. Pat.No. 7,612,087 (Patent document 2) and WO 2009/091856 (Patent document 3)have disclosed that certain kinds of diazabicyclooctane derivatives arepromising compounds in the treatment of infectious diseases as anantibiotic having non-β-lactam structure or a β-lactamase inhibitor. Asa process for preparing the same, in addition to the above-mentioneddocuments, the process disclosed in WO 2010/126820 A2 (Patent document4) has been known.

PRIOR ART DOCUMENTS Patent Documents

-   [Patent document 1] U.S. Pat. No. 7,112,592-   [Patent document 2] U.S. Pat. No. 7,612,087-   [Patent document 3] WO 2009/091856 A2-   [Patent document 4] WO 2010/126820 A2

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

The currently available β-lactamase inhibitors are insufficient toinhibit the incessantly increasing β-lactamase, and novel β-lactamaseinhibitors have been required today for the difficult treatment forbacterial infectious diseases caused by resistant bacteria which produceclass C β-lactamase, extended-spectrum β-lactamase (ESBL) belonging toclass A and D, or class A KPC-2 decomposing even carbapenem as a lastresort for β-lactam antibiotic.

Means for Solving the Problems

The present inventors have carried out research studies about a novelβ-lactamase inhibitor effective for the β-lactamase producing bacteriapresently causing the problems as mentioned above, particularly for theclass A, class C and class D β-lactamases, and as a result, a noveldiazabicyclooctane derivative represented by the formula (I) has beenfound. It has also been found that the compound of the present inventionpotently recover the antimicrobial activity of a β-lactam antibioticagainst the resistant bacteria when used in combination with theβ-lactam antibiotic.

Also, here has been established the preparation method of the compoundrepresented by the formula (II), which is included in the formula (I) ofthe present invention:

in the above formulae (I) and (II), A represents Ra(Rb)N— or RcO—; Brepresents NH or NC₁₋₆ alkyl; C represents benzyl, H or SO₃M, where Mrepresents H, an inorganic cation or an organic cation; Ra and Rb eachindependently represent H, C₁₋₆ alkyl or acyl; Rc represents C₁₋₆ alkylor a heterocyclyl; A may be modified by 0 to 4 substituents Fn1, wherethe substituent Fn1 may be substituted continuously; Fn1 represents C₁₋₆alkyl, O═ or Rg-(CH₂)₀₋₃—, where Rg represents a heterocyclyl, phenyl,heteroaryl, acyl, RdO₂S—, Re(Rf)N—, Re(Rf)NCO—, ReO—, ReOCO— or aprotective group, where Rd represents C₁₋₆ alkyl or MO—; Re and Rf eachindependently represent H or C₁₋₆ alkyl, and further, between Ra and Rb,between Rc and B, and between Re and Rf may be closed by the bonding toform a heterocyclyl having at least one nitrogen atom.

At first, for the research of a preparation method to obtain thecompound represented by the above-mentioned formula (II), even when themethod in which a phosgene equivalent and an amine are used as disclosedin U.S. Pat. Nos. 7,112,592 or 7,612,087 or the method in which thecompound is treated with triphosgene and a 10% aqueous phosphoric acidsolution as disclosed in WO 2009/133442 A1 or WO 2010/126820 A2 isapplied to the compound represented by the formula (IV-c):

in the above formula (IV-c), Rc and B have the same meanings as definedfor the compound of the formula (II), and OBn represents benzyloxy,

-   the compound represented by the above formula (IV-c) has    N-alkoxycarbamoyl showing weak acidity in the side chain at the    2-position, so that the compound having a diazabicyclooctane    structure represented by the following formula (IIa):

in the above formula (IIa), Rc and B have the same meanings as definedfor the compound of the formula (II), and OBn represents benzyloxy,

-   can be prepared only by an extremely minor yield.

Also, the method disclosed in WO 2009/133442 A1 or WO 2010/126820 A2introduces the side chain at the 2-position at the initial stage of thepreparation process, which is not so inexpensive, so that the method isnot necessarily efficient as a commercial manufacturing process, andestablishment of a preparation process which can be easilyindustrialized has been desired.

Thus, the present inventors have found the compounds represented by thefollowing formula (IV-a2), (IV-a3) or (IV-a4):

in the above formulae (IV-a2), (IV-a3) or (IV-a4), TFA representstrifluoroacetyl, Boc represents tert-butoxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy,

-   as more useful starting materials, and earnestly studied to lead    them to the compounds of the above formula (IV-c) and the above    formula (IIa).

As a result, here has been established the process for preparing acompound represented by the following formula (III):

in the above formula (III), Rc, B and M have the same meanings asdefined for the compound of the above formula (II),

-   which is included in the compound of the above formula (II).

That is, the present invention is directed to

-   (1) a diazabicyclooctane derivative represented by the following    formula (I):

in the above formula (I), A represents Ra(Rb)N— or RcO—; B represents NHor NC₁₋₆ alkyl; C represents benzyl, H or SO₃M, where M represents H, aninorganic cation or an organic cation; Ra and Rb each independentlyrepresent H, C₁₋₆ alkyl or acyl; Rc represents C₁₋₆ alkyl or aheterocyclyl; A may be modified by 0 to 4 substituents Fn1, where thesubstituent Fn1 may be substituted continuously; Fn1 represents C₁₋₆alkyl, O═ or Rg-(CH₂)₀₋₃—, where Rg represents a heterocyclyl, phenyl,heteroaryl, acyl, RdO2S—, Re(Rf)N—, Re(Rf)NCO—, ReO—, ReOCO— or aprotective group, where Rd represents C₁₋₆ alkyl or MO-; Re and Rf eachindependently represent H or C₁₋₆ alkyl, and further, between Ra and Rb,between Rc and B, and between Re and Rf may be closed by the bonding toform a heterocyclyl having at least one nitrogen atom, apharmaceutically acceptable salt thereof, or a solvate thereof.

Also, according to the other embodiment of the present invention, it isdirected to

-   (2) a diazabicyclooctane derivative represented by the following    formula (II):

in the above formula (II), Rc represents C₁₋₆ alkyl or a heterocyclyl; Brepresents NH or NC₁₋₆ alkyl; C represents benzyl, H or SO₃M, where Mrepresents H, an inorganic cation or an organic cation; Rc may bemodified by 0 to 4 substituents Fn1, where the substituent Fn1 may besubstituted continuously; Fn1 represents C₁₋₆ alkyl, O═ or Rg-(CH₂)₀₋₃—,where Rg represents a heterocyclyl, phenyl, heteroaryl, acyl, RdO2S—,Re(Rf)N—, Re(Rf)NCO—, ReO—, ReOCO— or a protective group, where Rdrepresents C₁₋₆ alkyl or MO—; Re and Rf each independently represent Hor C₁₋₆ alkyl, and further, between Rc and B, and between Re and Rf maybe closed by the bonding to form a heterocyclyl having at least onenitrogen atom,

-   a pharmaceutically acceptable salt thereof, or a solvate thereof,-   which is included in the above formula (I).

Also, according to the further embodiment of the present invention, itis directed to

-   (3) a novel diazabicyclooctane derivative represented by the    following formula (IIa):

in the above formula (IIa), OBn represents benzyloxy, and Rc and B havethe same meanings as defined for the above formula (II),

-   a pharmaceutically acceptable salt thereof or a solvate thereof,-   which is included in the above formula (II).

Also, according to still further embodiment of the present invention, itis directed to

-   (4) a diazabicyclooctane derivative represented by the following    formula (IIb):

in the above formula (IIb), Rc and B have the same meanings as definedfor the above formula (II),

-   a pharmaceutically acceptable salt thereof or a solvate thereof,-   which is included in the above formula (II).

Also, according to still further embodiment of the present invention, itis directed to

-   (5) a diazabicyclooctane derivative represented by the following    formula (III):

in the above formula (III), Rc, B and M have the same meanings asdefined for the above formula (II),

-   a pharmaceutically acceptable salt thereof, or a solvate thereof,-   which is included in the above formula (II).

Further, another embodiment of the present invention is directed to

-   (6) the compound of any one of the above (1) to (5), which is    represented by one of the following formulae:

in the above formulae, P² represents tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz) or H; P³ represents benzyl (Bn), H or SO₃M;where M represents H, sodium, pyridinium or tetrabutylammonium,

-   a pharmaceutically acceptable salt thereof or a solvate thereof.

Also, another embodiment of the present invention is directed to

-   (7) the compound of any one of the above (1) to (3), which is-   (2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-{[(2S)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N—{[(2R)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-[(2S)-azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,    or-   (2S,5R)—N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,    a pharmaceutically acceptable salt thereof, or a solvate thereof.

Also, according to another embodiment of the present invention, it isdirected to (8) a pharmaceutical composition comprising thediazabicyclooctane derivative represented by the above formula (I), apharmaceutically acceptable salt thereof or a solvate thereof, and,optionally, a pharmaceutically acceptable carrier.

Further, according to another embodiment of the present invention, it isdirected to (9) a pharmaceutical composition according to (8) foradministration in combination with a β-lactam antibiotic.

Moreover, according to another embodiment of the present invention, itis directed to (10) a pharmaceutical composition according to (8) or (9)for treating bacterial infection.

Also, according to still further embodiment of the present invention, itis directed to (11) a β-lactamase inhibitor comprising thediazabicyclooctane derivative represented by the above formula (I), apharmaceutically acceptable salt thereof or a solvate thereof.

According to still further embodiment of the present invention, it isdirected to (12) a pharmaceutical composition comprising the aboveβ-lactamase inhibitor, a β-lactam antibiotics, and, optionally, apharmaceutically acceptable carrier.

Moreover, according to still further embodiment of the presentinvention, provided is (13) a pharmaceutical composition comprising theabove β-lactamase inhibitor, a β-lactam antibiotic selected from thegroup consisting of ampicillin, amoxicillin, piperacillin, ticarcillin,flomoxef, cefotaxim, ceftriaxone, ceftazidime, cefepime, ceftaroline,ceftolozane, imipenem, meropenem, biapenem, doripenem, ertapenem andaztreonam, and, optionally, a pharmaceutically acceptable carrier.

Also, according to still further embodiment of the present invention, itis directed to a method for treating bacterial infection, and provided(14) the method for treating bacterial infection which comprisesadministering the above β-lactamase inhibitor and a β-lactam antibioticin combination.

Further, according to still further embodiment of the present invention,it is directed to a method for treating bacterial infection, andprovided (15) the method for treating bacterial infection whichcomprises administering the β-lactamase inhibitor, and a β-lactamantibiotic selected from the group consisting of ampicillin,amoxicillin, piperacillin, ticarcillin, flomoxef, cefotaxim,ceftriaxone, ceftazidime, cefepime, ceftaroline, ceftolozane, imipenem,meropenem, biapenem, doripenem, ertapenem and aztreonam, in combination.

Moreover, according to another embodiment of the present invention, itis directed to a method for treating bacterial infection, and providedthe method for treating a single or mixed bacterial infection caused byat least one of Escherichia coli, Klebsiella pneumoniae, Enterobactercloacae, Citrobacter freundii, Serratia marcescens, Morganella morganii,Pseudomonas aeruginosa and Acinetobacter baumannii, which comprisesadministering the β-lactamase inhibitor, and a β-lactam antibioticselected from the group consisting of ampicillin, amoxicillin,piperacillin, ticarcillin, flomoxef, cefotaxim, ceftriaxone,ceftazidime, cefepime, ceftaroline, ceftolozane, imipenem, meropenem,biapenem, doripenem, ertapenem and aztreonam, in combination.

Further, according to another embodiment of the present invention, it isdirected to a process for preparing the compound represented by thefollowing formula (III):

in the above formula (III), Rc, B and M have the same meanings asdefined for the above formula (II),

-   which is included in the above formula (II), which comprises-   (16) subjecting to coupling a compound represented by the following    formula (IV-a):

in the above formula (1V-a), P¹ represents a protective group which canbe removed by an acid, a base or a nucleophilic agent; and OBnrepresents benzyloxy,

-   with a compound: RcOBH using an active ester, an active amide or a    dehydration condensing agent to prepare a compound represented by    the following formula (IV-b):

in the above formula (IV-b), P¹ represents a protective group which canbe removed by an acid, a base or a nucleophilic agent; Rc and B have thesame meanings as defined for

-   the above formula (II), and OBn represents benzyloxy,-   deprotecting P¹ which is a protective group to prepare a compound    represented by the following formula (IV-c):

in the above formula (IV-c), Rc and B have the same meanings as definedfor the above formula (II), and OBn represents benzyloxy,

-   silylating the compound in the reaction system, and then, subjecting    to intramolecular urea formation reaction to prepare a compound    represented by the following formula (IIa):

in the above formula (IIa), Rc and B have the same meanings as definedfor the above formula (II), and OBn represents benzyloxy,

-   then, removing the benzyl of the benzyloxy at the 6-position using a    hydrogenolysis catalyst under hydrogen atmosphere to prepare a    compound represented by the following formula (IIb):

in the above formula (IIb), Rc and B have the same meanings as definedfor the above formula (II),

-   and sulfating the hydroxyl group at the 6-position in the presence    of a base, and, if necessary, deprotecting the protective group in    the side chain: RcOB— to prepare the compound represented by the    formula (III).

Moreover, according to another embodiment of the present invention, itis directed to a process for preparing the compound represented by thefollowing formula (IIa):

in the above formula (IIa), OBn represents benzyloxy, and Rc and B havethe same meanings as defined for the above formula (II),

-   which is included in the above formula (II), which comprises-   (17) subjecting to coupling a compound represented by the following    formula (IV-a):

in the above formula (IV-a), P¹ represents a protective group which canbe removed by an acid, a base or a nucleophilic agent; and OBnrepresents benzyloxy,

-   with a compound: RcOBH using an active ester, an active amide or a    dehydration condensing a agent to prepare a compound represented by    the following formula (IV-b):

in the above formula (IV-b), P¹ represents a protective group which canbe removed by an acid, a base or a nucleophilic agent; Rc and B have thesame meanings as defined for

-   the above formula (II), and OBn represents benzyloxy,-   deprotecting P¹ which is a protective group to prepare a compound    represented by the following formula (IV-c):

in the above formula (IV-c), Rc and B have the same meanings as definedfor the above formula (II), and OBn represents benzyloxy,

-   silylating the compound in the reaction system, and then, subjecting    to intramolecular urea formation reaction to prepare a compound    represented by the formula (IIa).

Moreover, according to the other embodiment of the present invention, itis directed to a process for preparing the compound represented by thefollowing formula (IIa):

in the above formula (IIa), OBn represents benzyloxy, and Rc and B havethe same meanings as defined for the above formula (II),

-   which is included in the above formula (II), which comprises-   (18) silylating the compound represented by the following formula    (IV-c):

in the above formula (IV-c), Rc and B have the same meanings as definedfor the above formula (II), and OBn represents benzyloxy,

-   in the reaction system, and then, subjecting to intramolecular urea    formation reaction to prepare a compound represented by the formula    (IIa).

Also, according to another embodiment of the present invention, it isdirected to a process for preparing the compound represented by thefollowing formula (III):

in the above formula (III), Rc, B and M have the same meanings asdefined for the above formula (II),

-   which is included in the above formula (II), which comprises-   (19) removing the benzyl of the benzyloxy at the 6-position of a    compound represented by the following formula (IIa):

in the above formula (IIa), Rc and B have the same meanings as definedfor the above formula (II), and OBn represents benzyloxy,

-   using a hydrogenolysis catalyst under hydrogen atmosphere to prepare    a compound represented by the following formula (IIb):

in the above formula (IIb), Rc and B have the same meanings as definedfor the above formula (II),

-   and sulfating the hydroxyl group at the 6-position in the presence    of a base, and, if necessary, deprotecting the protective group in    the side chain: RcOB— to prepare the compound represented by the    formula (III).

Further, according to another embodiment of the present invention, it isdirected to a process for preparing(2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamiderepresented by the following formula (III-059):

which comprises

-   (20) among the compounds represented by the following formulae    (IV-a2), (IV-a3) and (IV-a4):

in the above formula (IV-a2), (IV-a3) or (IV-a4), TFA representstrifluoroacetyl, Boc represents tert-butoxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy,

-   subjecting to coupling the compound represented by the formula    (IV-a2) or (IV-a4) with tert-butyl 2-(aminooxy)ethylcarbamate using    an active ester, an active amide or a dehydration condensing agent,    or-   subjecting to coupling the compound represented by the formula    (IV-a3) with benzyl 2-(aminooxy)ethylcarbamate using an active    ester, an active amide or a dehydration condensing agent,-   to prepare a compound represented by the following formula    (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059):

in the above formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or(IV-b4-Boc-059), TFA represents trifluoroacetyl, Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy,

-   removing the trifluoroacetyl of the compound represented by the    formula (IV-b2-Boc-059) by the treatment with a base to prepare a    compound represented by the following formula (IV-c-Boc-059):

in the above formula (IV-c-Boc-059) or (IV-c-Cbz-059), Boc representstert-butoxy-carbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy,

-   removing the tert-butoxycarbonyl of the compound represented by the    formula (IV-b3-Cbz-059) by an acid treatment to prepare a compound    represented by the above formula (IV-c-Cbz-059), or-   removing the 2-trimethylsilylethoxycarbonyl of the compound    represented by the formula (IV-b4-Boc-059) by a fluoride to prepare    a compound represented by the above formula (IV-c-Boc-059),-   then, after silylating the above-mentioned (IV-c-Boc-059) or    (IV-c-Cbz-059) in the reaction system, subjecting to intramolecular    urea formation reaction to prepare a compound represented by the    following formula (IIa-Boc-059) or (IIa-Cbz-059):

in the above formula (IIa-Boc-059) or (IIa-Cbz-059), Boc representstert-butoxy-carbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy,

-   removing the benzyl of the benzyloxy at the 6-position of the    compound represented by the formula (IIa-Boc-059) using a    hydrogenolysis catalyst under hydrogen atmosphere, or-   removing the benzyl of the benzyloxy at the 6-position of the    compound represented by the formula (IIa-Cbz-059) using a    hydrogenolysis catalyst under hydrogen atmosphere, and    simultaneously tert-butoxycarbonylating the same in the presence of    di-tert-butoxydicarbonate to prepare a compound represented by the    following formula (IIb-Boc-059):

in the above formula (IIb-Boc-059), Boc represents tert-butoxycarbonyl,sulfating the hydroxyl group at the 6-position to prepare a compoundrepresented by the following formula (III-Boc-059):

in the above formula (III-Boc-059), Boc represents tert-butoxycarbonyl,and M represents H, pyridinium, sodium, or tetrabutylammonium,

-   and deprotecting the tert-butoxycarbonyl by an acid treatment to    prepare the compound represented by the formula (III-059).

Also, according to another embodiment of the present invention, it isdirected to a process for preparing tert-butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octo-2-yl]carbonyl}amino)oxy]ethyl}carbamate,or benzyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octo-2-yl]carbonyl}amino)oxy]-ethyl}carbamaterepresented by the following formula (IIa-Boc-059) or (IIa-Cbz-059):

in the above formula (IIa-Boc-059) or (IIa-Cbz-059), Boc representstert-butoxy-carbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, which comprises

-   (21) among the compounds represented by the following formulae    (IV-a2), (IV-a3) and (IV-a4):

in the above formula (IV-a2), (IV-a3) or (IV-a4), TFA representstrifluoroacetyl, Boc represents tert-butoxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy,

-   subjecting to coupling each of the compounds represented by the    formulae (IV-a2) and (IV-a4) using tert-butyl    2-(aminooxy)ethylcarbamate,    1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride and    1-hydroxybenzotriazolemonohydrate in combination,-   subjecting to coupling the compound represented by the formula    (IV-a3) using benzyl 2-(aminooxy)ethylcarbamate,    1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and    1-hydroxybenzotriazolemonohydrate in combination,-   to prepare a compound represented by the following formula    (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059):

in the above formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or(IV-b4-Boc-059), TFA represents trifluoroacetyl, Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy,

-   removing the trifluoroacetyl of the compound represented by the    formula (IV-b2-Boc-059) by using a base selected from lithium    hydroxide, sodium hydroxide and potassium hydroxide to prepare a    compound represented by the following formula (IV-c-Boc-059):

in the above formula (IV-c-Boc-059) or (IV-c-Cbz-059), Boc representstert-butoxy-carbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, removing the tert-butoxycarbonyl of the compoundrepresented by the formula (IV-b3-Cbz-059) using an acid selected fromhydrochloric acid, sulfuric acid, methanesulfonic acid andtrifluoroacetic acid to prepare a compound represented by the aboveformula (IV-c-Cbz-059), or

-   removing the 2-trimethylsilylethoxycarbonyl of the compound    represented by the formula (IV-b4-Boc-059) using tetrabutylammonium    fluoride to prepare a compound represented by the above formula    (IV-c-Boc-059), and-   silylating the compound represented by the above formula    (IV-c-Boc-059) or (IV-c-Cbz-059) using chlorotrialkylsilane in the    reaction system and subsequently subjecting to intramolecular urea    formation reaction using phosgene or diphosgene to prepare the    compound represented by the formula (IIa-Boc-059) or (IIa-Cbz-059).

According to another embodiment of the present invention, it is directedto a process for preparing tert-butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo-[3.2.1]octo-2-yl]carbonyl}amino)oxy]ethyl}carbamate,or benzyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamaterepresented by the following formula (IIa-Boc-059) or (IIa-Cbz-059):

in the above formula (IIa-Boc-059) or (IIa-Cbz-059), Boc representstert-butoxy-carbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, which comprises

-   (22) silylating a compound represented by the following formula    (IV-c-Boc-059) or (IV-c-Cbz-059):

in the above formula (IV-c-Boc-059) or (IV-c-Cbz-059), Boc representstert-butoxy-carbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, using chlorotrimethylsilane in the reactionsystem, and subsequently subjecting to intramolecular urea formationreaction using phosgene or diphosgene to prepare the compoundrepresented by the formula (IIa-Boc-059) or (IIa-Cbz-059).

Further, according to another embodiment of the present invention, it isdirected to a process for preparing(2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamiderepresented by the following formula (III-059):

which comprises

-   (23) among the compounds represented by the following formulae    (IIa-Boc-059) and (IIa-Cbz-059):

in the above formula (IIa-Boc-059) or (IIa-Cbz-059), Boc representstert-butoxy-carbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, removing the benzyl of the benzyloxy at the6-position of the compound represented by the formula (IIa-Boc-059)using palladium-carbon under hydrogen atmosphere, or removing the benzylof the benzyloxy at the 6-position of the compound represented by theformula (IIa-Cbz-059) using palladium-carbon under hydrogen atmospherein the presence of di-tert-butoxydicarbonate, and simultaneouslysubjecting to tert-butoxy-carbonylation to prepare a compoundrepresented by the following formula (IIb-Boc-059):

in the above formula (IIb-Boc-059), Boc represents tert-butoxycarbonyl,sulfating the hydroxyl group at the 6-position by a sulfurtrioxide-pyridine complex in the presence of pyridine, 2-picoline or2,6-lutidine, to prepare a compound represented by the following formula(III-Boc-059):

in the above formula (III-Boc-059), Boc represents tert-butoxycarbonyl,and M represents H, pyridinium, sodium or tetrabutylammonium,

-   and deprotecting the tert-butoxycarbonyl by an acid selected from    hydrochloric acid, sulfuric acid, methanesulfonic acid,    trifluoroacetic acid and tetrafluoroboric acid to prepare the    compound represented by the formula (III-059).

Also, according to another embodiment of the present invention, it isdirected to a process for preparing tert-butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}aminoloxy]ethyl}carbamaterepresented by the following formula (IIa-Boc-059):

in the above formula (IIa-Boc-059), Boc represents tert-butoxycarbonyl,and OBn represents benzyloxy,

-   which comprises-   (24) silylating a compound represented by the following formula    (IV-c-Boc-059):

in the above formula (IV-c-Boc-059), Boc represents tert-butoxycarbonyl,and OBn represents benzyloxy,

-   using triethylamine and chlorotrimethylsilane in the reaction    system, and subsequently subjecting to intramolecular urea formation    reaction using phosgene or diphosgene with a catalytic amount of    4-dimethylaminepyridine to prepare the compound represented by the    formula (IIa-Boc-059).

In addition, according to the other embodiment of the present invention,it is directed to a process for preparing(2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamiderepresented by the following formula (III-059):

which comprises,

-   (25) removing the benzyl of the benzyloxy at the 6-position of a    compound represented by the following formula (IIa-Boc-059):

in the above formula (IIa-Boc-059), Boc represents tert-butoxycarbonyl,and OBn represents benzyloxy,

-   using palladium-carbon under hydrogen atmosphere to prepare a    compound represented by the following formula (IIb-Boc-059):

in the above formula (IIb-Boc-059), Boc represents tert-butoxycarbonyl,

-   sulfating the hydroxyl group at the 6-position using a sulfur    trioxide-pyridine complex in the presence of pyridine, 2-picoline or    2,6-lutidine to prepare a compound represented by the following    formula (III-Boc-059):

in the above formula (III-Boc-059), Boc represents tert-butoxycarbonyl,and M represents H, pyridinium, sodium or tetrabutylammonium,

-   and deprotecting the tert-butoxycarbonyl with an acid selected from    hydrochloric acid, sulfuric acid, methanesulfonic acid,    trifluoroacetic acid and tetrafluoroboric acid to prepare the    compound represented by the formula (III-059).

Also, another embodiment of the present invention is directed to aprocess for preparing (2S,5R)-methyl5-(benzyloxyamino)piperidine-2-carboxylate or a hydro-chloride thereof,which comprises (26) subjecting (2S,5S)-5-hydroxypiperidine-2-carboxylicacid or a hydrochloride thereof to methyl esterification,trifluoroacetylation, benzyloxyamination of the C5 hydroxyl group andremoval of trifluoroacetyl each without subjecting to purification,followed by crystallization as a hydrochloride thereby isolating andpurifying (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate or ahydrochloride thereof.

Further, another embodiment of the present invention is directed to (27)the compounds represented by the formulae:

in the above formulae, TFA represents trifluoroacetyl, OMe representsmethoxy, Boc represents tert-butoxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy.

EFFECTS OF THE INVENTION

The novel diazabicyclooctane derivatives represented by the aboveformula (I) provided by the present invention show potent inhibitoryactivity against various kinds of β-lactamases. In particular, it showspotent inhibitory activity against class A, class C and class Dβ-lactamases. More specifically, it shows potent inhibitory activityagainst class C β-lactamase, extended-spectrum β-lactamase (ESBL), andKPC-2 β-lactamase, and antimicrobial activity of the existing β-lactamantibiotic against the bacteria producing these β-lactamases resistantto the β-lactam antibiotic can be potently recovered in combination withthe compound of this invention.

In addition, the process for preparing the compound represented by thefollowing formula (II):

in the above formula (II), Rc represents C₁₋₆ alkyl or a heterocyclyl; Brepresents NH or NC₁₋₆ alkyl; C represents benzyl, H or SO₃M, where Mrepresents H, an inorganic cation or an organic cation; Rc may bemodified by 0 to 4 substituents Fn1, where the substituent Fn1 may besubstituted continuously; Fn1 represents C₁₋₆ alkyl, O═ or Rg-(CH₂)₀₋₃—,where Rg represents a heterocyclyl, phenyl, heteroaryl, acyl, RdO₂S—,Re(Rf)N—, Re(Rf)NCO—, ReO—, ReOCO— or a protective group, where Rdrepresents C₁₋₆ alkyl or MO—; Re and Rf each independently represent Hor C₁₋₆ alkyl, and further, between Rc and B, and between Re and Rf maybe closed by the bonding to form a heterocyclyl having at least onenitrogen atom,

-   which is included in the compound of the formula (I) provided by the    present invention, is a preparation process having higher usefulness    as a preparation process for commercialization.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows antibacterial activities to 5 strains of KPC-2 or 3producing strain, K. pneumoniae.

FIG. 2 shows antibacterial activities to 5 strains of AmpC constitutiveexpression, P. aeruginosa.

FIG. 3 shows antibacterial activities to 5 strains of AmpC constitutiveexpression, Enterobacteriaceae.

FIG. 4 shows antibacterial activities to 5 strains of IMP typemetallo-β-lactamase producing strain, Enterobacteriaceae.

FIG. 5 shows antibacterial activities to 5 strains of CTX-M-15 (ESBL)producing strain, E. coli.

MODE FOR CARRYING OUT THE INVENTION

As mentioned above, the present invention is to provide a noveldiaza-bicyclooctane derivative represented by the following formula (I),a pharmaceutically acceptable salt thereof, or a solvate thereof, and aβ-lactamase inhibitor comprising the compound of the formula (I):

in the above formula (I), A represents Ra(Rb)N— or RcO—; B represents NHor NC₁₋₆ alkyl; C represents benzyl, H or SO₃M, where M represents H, aninorganic cation or an organic cation; Ra and Rb each independentlyrepresent H, C₁₋₆ alkyl or acyl; Rc represents C₁₋₆ alkyl or aheterocyclyl; A may be modified by 0 to 4 substituents Fn1, where thesubstituent Fn1 may be substituted continuously; Fn1 represents C₁₋₆alkyl, O═ or Rg-(CH₂)₀₋₃—, where Rg represents a heterocyclyl, phenyl,heteroaryl, acyl, RdO₂S—, Re(Rf)N—, Re(Rf)NCO—, ReO—, ReOCO— or aprotective group, where Rd represents C₁₋₆ alkyl or MO-; Re and Rf eachindependently represent H or C₁₋₆ alkyl, and further, between Ra and Rb,between Rc and B, and between Re and Rf may be closed by the bonding toform a heterocyclyl having at least one nitrogen atom.

In the following, the novel diazabicyclooctane derivatives representedby the formula (I) of the present invention and a process for preparingthe same, a β-lactamase inhibitor, and a use of the compound of thisinvention for the treatment of the bacterial infection will be explainedin detail, but the present invention is not limited by the scope of thedesignated specific examples.

The term “salt” used in the present specification means apharmaceutically acceptable salt, and there are a base-added saltcomprising an inorganic base or an organic base, and an acid-added saltcomprising an inorganic acid or an organic acid.

The terms “inorganic cation” mean an alkali metal or an alkaline earthmetal, etc., and the terms “organic cation” mean an ammonium salt formedfrom mono- to tri-substituted amine, and a quaternary ammonium saltformed from tetra-substituted amine or by substituted heteroaromaticring.

When “M” is H and the compound of the present invention has an aminogroup, cyclic amines or aromatic amines which can be protonated in themolecule, the amino group, cyclic amines or aromatic amines in themolecule behave as a protonated ammonium salt, and it can take the formof an intramolecular salt, which is also deemed to be a part of thecompound of the present invention. Further, when “M” is an organiccation and present in the molecule of the compound of the presentinvention as a quaternary ammonium salt, it can also take the form of anintramolecular salt, which is also deemed to be a part of the compoundof the present invention.

The term “modified” means to exchange H in A or in the substituent Fn1and bind with or by the substituent Fn1.

The terms “A may be modified by 0 to 4 substituents Fn1, and thesubstituent Fn1 may be substituted continuously.” mean that Fn1 whichmodifies A may be further modified by Fn1, and there may be mentionedA-(Fn1)₀₋₄, A-(Fn1)(Fn1)₀₋₃, A-(Fn1)₂(Fn1)₀₋₂, and A-(Fn1)₃(Fn1)₀₋₁,etc.

Specific examples of the “protective group” may be mentioned atrialkylsilyl and a carbamate type protective group, preferablytriisopropylsilyl, tert-butyldimethylsilyl, tert-butoxycarbonyl orbenzyloxycarbonyl, which is a protective group for an amino group and ahydroxyl group disclosed in Protective Groups in Organic Synthesis (T.W. Greene et al., Wiley, New York (1999)).

The solvent contained in the “solvate” may be water, methanol, ethanol,isopropanol, acetone and methyl ethyl ketone, more preferably water.

The terms “C₁₋₆ alkyl” mean an alkyl group having 1 to 6 carbon atoms,which may be straight, branched or cyclic.

The terms “acyl” mean formyl, benzoyl, phenylacetyl, C₁₋₆ alkylcarbonyl,heterocyclylcarbonyl, and heteroarylcarbonyl.

The terms “heterocyclyl” mean a 3 to 7-membered monocyclic saturatedheterocyclic ring or non-aromatic ring having 1 to 3 nitrogen atom(s),oxygen atom(s) and/or sulfur atom(s) in total.

The terms “heteroaryl” mean a 5 to 6-membered monocyclic heteroaromaticring having 1 to 4 nitrogen atom(s), oxygen atom(s) and/or sulfuratom(s) in total.

The terms “Ra(Rb)N—” and “Re(Rf)N—” mean an amino group substituted byRa and Rb, or Re and Rf.

The term “RcO—” means oxy bonded to Rc, i.e., alkoxy or heterocyclyloxy,and the term “ReO—” means oxy bonded to Re, i.e., alkoxy or hydroxy.

The term “RdO₂S—” means sulfonyl bonded to Rd.

The term “Re(Rf)NCO—” means carbonyl bonded to Re(Rf)N—.

The term “ReOCO—” means carbonyl bonded to ReO—.

The term “O═” means an oxo group.

Specific examples of the bases which form the “base-added salt” may bementioned lithium hydroxide, sodium hydroxide, potassium hydroxide,sodium hydrogen carbonate, potassium hydrogen carbonate, sodiumcarbonate, potassium carbonate, lithium carbonate, calcium carbonate,sodium acetate, potassium acetate, trisodium citrate, sodium dihydrogencitrate, tripotassium citrate, potassium dihydrogen citrate, ammonia,methylamine, ethylamine, dimethylamine, diethylamine, trimethyl-amine,triethylamine, N-methylmorpholine, ethanolamine and triethanolamine,etc., preferably sodium hydroxide, sodium hydrogen carbonate, sodiumcarbonate, sodium acetate, trisodium citrate, sodium dihydrogen citrateand triethanolamine, etc.

Specific examples of the acids which form the “acid-added salt” may bementioned hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, sulfuric acid, hemisulfuric acid, thiocyanic acid, acetic acid,butyric acid, propionic acid, cyclopentanepropionic acid, pivalic acid,heptanoic acid, hexanoic acid, 3-phenyl-propionic acid, undecanoic acid,lactic acid, oxalic acid, malonic acid, succinic acid, citric acid,tartaric acid, malic acid, maleic acid, fumaric acid, adipic acid,alginic acid, aspartic acid, benzoic acid, digluconic acid, nicotinicacid, pamoic acid, pectic acid, glucoheptanoic acid, glycerophosphoricacid, benzenesulfonic acid, tosylic acid, methanesulfonic acid,ethanesulfonic acid, camphorsulfonic acid, dodecylsulfuric acid,2-hydroxyethanesulfonic acid and 2-naphthalenesulfonic acid, etc.,preferably hydrochloric acid, sulfuric acid, acetic acid, lactic acid,malic acid, citric acid, methanesulfonic acid and tosylic acid, etc.

Specific examples of the “inorganic cation” include sodium, potassium,lithium, calcium, etc., preferably sodium and potassium.

Specific examples of the “organic cation” includes methylammonium,ethylammonium, dimethylammonium, diethylammonium, diisopropylammonium,pyridinium, trimethylammonium, triethylammonium, cyclohexylammonium,dicyclohexylammonium, diisopropylethylammonium, pyridinium,tetramethyl-ammonium, tetraethylammonium, tetrabutylammonium,triethylbenzylammonium, N,N′-dimethylimidazolium, N-methylpyridinium,etc., preferably pyridinium and tetrabutylammonium.

Specific examples of the “C₁₋₆ alkyl” include a C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, s-butyl, isobutyl,pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, neopentyl,1-methylbutyl, 2-methylbutyl, isopentyl and hexyl, a C₃₋₆ cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or amethyl group substituted by a C₃₋₅ cycloalkyl group such ascyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, preferablymethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopropyl,cyclobutyl, cyclopropylmethyl and cyclobutylmethyl.

Specific examples of the “heterocyclyl” include a group derived fromaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,tetrahydrofuran, tetrahydro-thiophene, imidazolidine, oxazolidine,thiazolidine, pyrazolidine, piperidine, tetrahydro-2H-pyran,tetrahydro-2H-thiopyran, hexahydropyridazine, piperazine, morpholine,thiomorpholine, 1,2-oxazolidine, 1,2-oxazinane, 1,4-dioxane,1,2-thiazinane, azepane, oxepane, thiepane, 1,4-diazepane,1,4-oxazepane, 1,4-thiazepane, 1,2,5-triazepane, 1,4,5-oxadiazepane,1,2,5-oxadiazepane, 1,4,5-thiadiazepane, 1,5,2-dioxazepane,1,5,2-oxathiazepane, 3,4-dihydro-2H-pyrrole, 4,5-dihydro-1H-pyrazole,4,5-dihydro-1H-imidazole, 4,5-dihydro-1,2-oxazole,4,5-dihydro-1,3-oxazole, 4,5-dihydro-1,3-thiazole,2,3,4,5-tetrahydropyridine, 1,2,3,6-tetrahydropyrazine,5,6-dihydro-4H-1,2-oxazine, 3,6-dihydro-2-H-1,4-oxazine, etc.,preferably a group derived from azetidine, pyrrolidine, tetrahydrofuran,piperidine, tetrahydro-2H-pyran, imidazolidine, oxazolidine,1,2-oxazolidine, hexahydropyridazine, piperazine, morpholine,1,2-oxazinane, azepane, 1,4-diazepane and 1,2-oxazepane. Specificexamples of the protective group for the “heterocyclyl” to which“tert-butoxycarbonyl or benzyloxycarbonyl is bonded” include a groupderived from 1-(tert-butoxycarbonyl)azetidine,1-(tert-butoxycarbonyl)pyrrolidine,1,3-di(tert-butoxycarbonyeimidazolidine,3-(tert-butoxycarbonyl)oxazolidine,1,3-di(tert-butoxycarbonyl)pyrazolidine,1-(tert-butoxycarbonyl)piperidine,1,2-di(tert-butoxycarbonyl)hexahydropyridazine,1,4-di(tert-butoxycarbonyl)piperazine,4-(tert-butoxycarbonyl)morpholine,2-(tert-butoxycarbonyl)-1,2-oxazolidine,2-(tert-butoxycarbonyl)-1,2-oxazinane, 1-(tert-butoxycarbonyl)azepane,1,4-di(tert-butoxycarbonyl)-1,4-diazepane,1-(benzyloxycarbonyl)azetidine, 1-(benzyloxycarbonyl)pyrrolidine,1,3-di(benzyloxycarbonyl)imidazolidine,3-(benzyloxycarbonyl)oxazolidine, 1,3-di(benzyloxycarbonyl)pyrazolidine,1-(benzyloxycarbonyl)piperidine,1,2-di(benzyloxycarbonyl)hexahydropyridazine,1,4-di(benzyloxycarbonyl)piperazine, 4-(benzyloxycarbonyl)morpholine,2-(benzyloxycarbonyl)-1,2-oxazolidine,2-(benzyloxycarbonyl)-1,2-oxazinane, 1-(benzyloxycarbonyl)azepane,1,4-dnbenzyloxycarbonyl)-1,4-diazepane, etc., and it is natural thatspecific examples having the above protective group are included in thespecific examples having heterocyclyl to be described later.

Specific examples of the “heteroaryl” include a group derived frompyrrole, furan, thiophene, pyrazole, imidazole, 1,2-oxazole,1,3-oxazole, 1,2-thiazole, 1,3-thiazole, 1,2,3-triazole, 1,2,4-triazole,1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole,1,3,4-thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, 1,2,4-triazine, 1,3,5-triazine, etc., preferably a groupderived from pyrrole, furan, imidazole, oxazole and pyridine.

Specific examples of the protective group for the “heteroaryl” to which“tert-butoxycarbonyl or benzyloxycarbonyl is bonded” include a groupderived from 1-tert-butoxycarbonylpyrrole,1-tert-butoxycarbonylpyrazole, 1-tert-butoxycarbonylimidazole,1-tert-butoxycarbonyl-1,2,3-triazole,1-tert-butoxycarbonyl-1,2,4-triazole, 1-tert-butoxycarbonyltetrazole,1-benzyloxycarbonylpyrrole, 1-benzyloxycarbonylpyrazole,1-benzyloxycarbonylimidazole, 1-benzyloxycarbonyl-1,2,3-triazole,1-benzyloxycarbonyl-1,2,4-triazole, 1-benzyloxycarbonyltetrazole, etc.,and it is natural that specific examples having the above protectivegroup are included in the specific examples having heteroaryl to bedescribed later.

Specific examples of the “C₁₋₆alkylcarbonyl” include acetyl, propanoyl,butanoyl, isobutanoyl, pentanoyl, 2,2-dimethylpropanoyl,2-methylbutanoyl, 3-methylbutanoyl, hexanoyl, cyclopropanecarbonyl,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,2-cyclopropylacetyl, 2-cyclobutylacetyl, 2-cyclopentylacetyl, etc.

Specific examples of the “heterocyclylcarbonyl” includeaziridin-2-ylcarbonyl, oxiran-2-ylcarbonyl, thiiran-2-ylcarbonyl,azetidin-2-ylcarbonyl, azetidin-3-ylcarbonyl, oxetan-2-ylcarbonyl,oxetan-3-ylcarbonyl, thietan-2-ylcarbonyl, thietan-3-ylcarbonyl,pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl,tetrahydrofuran-2-ylcarbonyl, tetrahydrofuran-3-ylcarbonyl,tetrahydrothiophen-2-ylcarbonyl, tetrahydrothiophen-3-ylcarbonyl,pyrazolidin-3-ylcarbonyl, pyrazolidin-4-ylcarbonyl,1,2-oxazolidin-3-ylcarbonyl, 1,2-oxazolidin-4-ylcarbonyl,1,2-oxazolidin-5-ylcarbonyl, piperidin-2-ylcarbonyl,piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl,tetrahydro-2H-pyran-2-ylcarbonyl, tetrahydro-2H-pyran-3-ylcarbonyl,tetrahydro-2H-pyran-4-ylcarbonyl, tetrahydro-2H-thiopyran-2-ylcarbonyl,tetrahydro-2H-thiopyran-3-ylcarbonyl,tetrahydro-2H-thiopyran-4-ylcarbonyl, hexahydropyridazin-3-ylcarbonyl,hexahydropyridazin-4-ylcarbonyl, piperazin-2-ylcarbonyl,morpholin-2-ylcarbonyl, morpholin-3-ylcarbonyl,thiomorpholin-2-ylcarbonyl, thiomorpholin-3-ylcarbonyl,1,2-oxazinan-3-ylcarbonyl, 1,2-oxazinan-4-ylcarbonyl,1,2-oxazinan-5-ylcarbonyl, 1,2-oxazinan-6-ylcarbonyl,1,4-dioxan-2-ylcarbonyl, 1,2-thiazinan-3-ylcarbonyl,1,2-thiazinan-4-ylcarbonyl, 1,2-thiazinan-5-ylcarbonyl,1,2-thiazinan-6-ylcarbonyl, azepan-2-ylcarbonyl, azepan-3-ylcarbonyl,azepan-4-ylcarbonyl, oxepan-2-ylcarbonyl, oxepan-3-ylcarbonyl,oxepan-4-ylcarbonyl, thiepan-2-ylcarbonyl, thiepan-3-ylcarbonyl,thiepan-4-ylcarbonyl, 1,4-diazepan-2-ylcarbonyl,1,4-diazepan-5-ylcarbonyl, 1,4-diazepan-6-ylcarbonyl,1,4-oxazepan-2-ylcarbonyl, 1,4-oxazepan-3-ylcarbonyl,1,4-oxazepan-5-ylcarbonyl, 1,4-oxazepan-6-ylcarbonyl,1,4-oxazepan-7-ylcarbonyl, 1,4-thiazepan-2-ylcarbonyl,1,4-thiazepan-3-ylcarbonyl, 1,4-thiazepan-5-ylcarbonyl,1,4-thiazepan-6-ylcarbonyl, 1,4-thiazepan-7-ylcarbonyl,1,2,5-triazepan-3-ylcarbonyl, 1,2,5-triazepan-4-ylcarbonyl,1,4,5-oxadiazepan-2-ylcarbonyl, 1,4,5-oxadiazepan-3-ylcarbonyl,1,2,5-oxadiazepan-3-ylcarbonyl, 1,2,5-oxadiazepan-4-ylcarbonyl,1,2,5-oxadiazepan-6-ylcarbonyl, 1,2,5-oxadiazepan-7-ylcarbonyl,1,4,5-thiadiazepan-2-ylcarbonyl, 1,4,5-thiadiazepan-3-ylcarbonyl,1,5,2-dioxazepan-3-ylcarbonyl, 1,5,2-dioxazepan-4-ylcarbonyl,1,5,2-dioxazepan-6-ylcarbonyl, 1,5,2-dioxazepan-7-ylcarbonyl,1,5,2-oxathiazepan-3-ylcarbonyl, 1,5,2-oxathiazepan-4-ylcarbonyl,1,5,2-oxathiazepan-6-ylcarbonyl, 1,5,2-oxathiazepan-7-ylcarbonyl, etc.It is natural that above specific examples include those to whichtert-butoxycarbonyl or benzyloxycarbonyl is bonded as a protectivegroup.

Specific examples of the “heteroarylcarbonyl” includepyrrol-2-ylcarbonyl, pyrrol-3-ylcarbonyl, furan-2-ylcarbonyl,furan-3-ylcarbonyl, thiophen-2-ylcarbonyl, thiophen-3-ylcarbonyl,pyrazol-3-ylcarbonyl, pyrazol-4-ylcarbonyl, imidazol-2-ylcarbonyl,imidazol-4-ylcarbonyl, 1,2-oxazol-3-ylcarbonyl, 1,2-oxazol-4-ylcarbonyl,1,2-oxazol-5-ylcarbonyl, 1,3-oxazol-2-ylcarbonyl,1,3-oxazol-4-ylcarbonyl, 1,3-oxazol-5-ylcarbonyl,1,2-thiazol-3-ylcarbonyl, 1,2-thiazol-4-ylcarbonyl,1,2-thiazol-5-ylcarbonyl, 1,3-thiazol-2-ylcarbonyl,1,3-thiazol-4-ylcarbonyl, 1,3-thiazol-5-ylcarbonyl,1,2,3-triazol-4-ylcarbonyl, 1,2,3-oxadiazol-4-ylcarbonyl,1,2,3-oxadiazol-5-ylcarbonyl, 1,2,3-thiadiazol-4-ylcarbonyl,1,2,3-thiadiazol-5-ylcarbonyl, 1,2,4-triazol-3-ylcarbonyl,1,3,4-oxadiazol-2-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl,tetrazol-5-ylcarbonyl, pyridin-2-ylcarbonyl, pyridin-3-ylcarbonyl,pyridin-4-ylcarbonyl, pyridazin-3-ylcarbonyl, pyridazin-4-ylcarbonyl,pyrimidin-2-ylcarbonyl, pyrimidin-4-ylcarbonyl, pyrimidin-5-ylcarbonyl,pyrazin-2-ylcarbonyl, 1,2,4-triazin-3-ylcarbonyl,1,2,4-triazin-5-ylcarbonyl, 1,2,4-triazin-6-ylcarbonyl,1,3,5-triazin-2-ylcarbonyl, etc. It is natural that above specificexamples include those to which tert-butoxycarbonyl or benzyloxycarbonylis bonded as a protective group.

To the above “acyl”, formyl, benzoyl, or phenylacetyl is added, andpreferred are formyl, benzoyl, acetyl, phenylacetyl, propanoyl,butanoyl, 2-methylpropanoyl, 2,2-dimethylpropanoyl,azetidin-2-ylcarbonyl, azetidin-3-ylcarbonyl, pyrrolidin-2-ylcarbonyl,pyrrolidin-3-ylcarbonyl, tetrahydrofuran-3-ylcarbonyl,piperidin-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl,tetrahydro-2H-pyran-2-ylcarbonyl, tetrahydro-2H-pyran-3-ylcarbonyl,tetrahydro-2H-pyran-4-ylcarbonyl, furan-2-ylcarbonyl,1,3-oxazol-2-ylcarbonyl, 1,3-oxazol-4-ylcarbonyl, pyridin-2-ylcarbonyl,pyridin-3-ylcarbonyl, and pyridin-4-ylcarbonyl.

Specific examples of Re(Rf)N— include amino, methylamino, ethylamino,propylamino, isopropylamino, butylamino, tert-butylamino, s-butylamino,isobutylamino, pentylamino, 1,1-dimethylpropylamino,1,2-dimethylpropylamino, neopentylamino, 1-methylbutylamino,2-methylbutylamino, isopentylamino, hexylamino, N,N-dimethylamino,N,N-diethylamino, N,N-dipropylamino, N,N-di(isopropyl)amino,N,N-dibutylamino, N,N-di(tert-butyl)amino, N,N-di(s-butyl)amino,N,N-di(isobutyl)amino, N,N-dipentylamino,N,N-di(1,1-dimethylpropyl)amino, N,N-di(1,2-dimethylpropyl)amino,N,N-di(neopentyl)amino, N,N-di(1-methylbutyl)amino,N,N-di(2-methylbutyl)amino, N,N-di(isopentyl)amino, N,N-di(hexyl)amino,etc., preferably amino, methylamino, ethylamino, propylamino,isopropylamino, N,N-dimethylamino, and N,N-diethylamino It is naturalthat the above specific examples include those protected bytert-butoxycarbonyl or benzyloxycarbonyl as a protective group.

Specific examples of Re(Rf)NCO— include aminocarbonyl,methylamino-carbonyl, ethylaminocarbonyl, propylaminocarbonyl,isopropylaminocarbonyl, butylaminocarbonyl, tert-butylaminocarbonyl,s-butylaminocarbonyl, isobutylamino-carbonyl, pentylaminocarbonyl,1,1-dimethylpropylaminocarbonyl, 1,2-dimethyl-propylaminocarbonyl,neopentylaminocarbonyl, 1-methylbutylaminocarbonyl,2-methylbutylaminocarbonyl, isopentylaminocarbonyl, hexylaminocarbonyl,N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl,N,N-dipropylaminocarbonyl, N,N-di(isopropyl)aminocarbonyl,N,N-dibutylaminocarbonyl, N,N-di(tert-butyl)amino-carbonyl,N,N-di(s-butyl)aminocarbonyl, N,N-di(isobutyl)aminocarbonyl,N,N-dipentylaminocarbonyl, N,N-di(1,1-dimethylpropyl)aminocarbonyl,N,N-di(1,2-dimethylpropyl)aminocarbonyl, N,N-di(neopentyl)aminocarbonyl,N,N-di(1-methyl-butyl)aminocarbonyl, N,N-di(2-methylbutyl)aminocarbonyl,N,N-di(isopentyl)amino-carbonyl, etc., which are derived from specificexamples of Re(Rf)N— described above, preferably dimethylaminocarbonylor diethylaminocarbonyl.

Specific examples of ReO— include hydroxy, methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, s-butoxy, isobutoxy, pentoxy,1,1-dimethylpropoxy, 1,2-dimethylpropoxy, neopentoxy, 1-methylbutoxy,2-methylbutoxy, isopentoxy, hexyloxy, benzyloxy, cyclopropoxy,cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy,cyclobutylmethoxy, cyclopentylmethoxy, etc., preferably hydroxy,methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, cyclopropoxy andcyclobutyl-methoxy. It is natural that the above hydroxy includes thoseto which triisopropylsilyl included in trialkylsilyloxy as a protectivegroup is bonded.

Specific examples of ReOCO— include methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, s-butoxycarbonyl, isobutoxycarbonyl,pentoxycarbonyl, 1,1-dimethylpropoxycarbonyl,1,2-dimethylpropoxycarbonyl, neopentoxycarbonyl, 1-methylbutoxycarbonyl,2-methylbutoxycarbonyl, isopentoxycarbonyl, hexyloxycarbonyl, etc.,which are derived from the specific examples of ReO— described above,preferably methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, andbenzyloxycarbonyl, methoxycarbonyl modified by phenyl which is definedby Fn1.

Specific examples of RdO₂S— include methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl,s-butylsulfonyl, isobutylsulfonyl, pentylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropyl-sulfonyl,neopentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl,isopentylsulfonyl, hexylsulfonyl, cyclopropanesulfonyl,cyclobutanesulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl,cyclopropylmethanesulfonyl, cyclobutyl-methanesulfonyl,cyclopentylmethanesulfonyl, etc., preferably sulfoxy andmethanesulfonyl.

Among specific examples of Ra(Rb)N— comprising the above C₁₋₆ alkyl,acyl and Re(Rf)N—, preferred are amino, methylamino, ethylamino,propylamino, isopropylamino, tert-butylamino, isobutylamino,N,N-dimethylamino, N,N-diethylamino, N,N-di(isopropyl)amino,acetylamino, propanoylamino, isobutanoylamino, phenylacetylamino,benzoylamino, [(azetidin-2yl)carbonyl]amino,[(azetidin-3-yl)carbonyl]amino, [(pyrrolidin-2-yl)carbonyl]amino,[(pyrrolidin-3-yl)carbonyl]amino, [(tetrahydrofuran-3-yl)carbonyl]amino,[(tetrahydrothiophen-3-yl)carbonyl]amino,[(pyrazolidin-3-yl)carbonyl]amino, [(pyrazolidin-4-yl)carbonyl]amino,[(1,2-oxazolidin-3-yl)carbonyl]amino, [(piperidin-2-yl)carbonyl]-amino,[(piperidin-3-yl)carbonyl]amino, [(piperidin-4-yl)carbonyl]amino,[(tetrahydro-2H-pyran-2-yl)carbonyl]amino,[(tetrahydro-2H-pyran-4-yl)carbonyl]amino,[(tetrahydro-2H-thiopyran-4-yl)carbonyl]amino,[(hexahydropyridazin-3-yl)carbonyl]-amino,[(hexahydropyridazin-4-yl)carbonyl]amino,[(piperazin-2-yl)carbonyl]amino, [(morpholin-2-yl)carbonyl]amino,[(morpholin-3-yl)carbonyl]amino, [(thiomorpholin-2-yl)carbonyl]amino,[(thiomorpholin-3-yl)carbonyl]amino, [(1,2-oxazinan-3-yl)carbonyl]amino,[(azepan-2-yl)carbonyl]amino, [(azepan-4-yl)carbonyl]amino,[(oxepan-2-yl)carbonyl]amino, [(oxepan-4-yl)carbonyl]amino,[(1,4-diazepan-2-yl)carbonyl]amino, [(1,4-diazepan-6-yl)carbonyl]amino,pyrrol-2-ylcarbonylamino, pyrrol-3-ylcarbonylamino,furan-2-ylcarbonylamino, furan-3-ylcarbonylamino,pyrazol-3-ylcarbonylamino, pyrazol-4-ylcarbonylamino,imidazol-2-ylcarbonylamino, imidazol-4-ylcarbonylamino,1,2-oxazol-3-ylcarbonylamino, 1,2-oxazol-4-ylcarbonylamino,1,2-oxazol-5-ylcarbonylamino, 1,3-oxazol-2-ylcarbonylamino,1,3-oxazol-4-ylcarbonyl-amino, 1,3-oxazol-5-ylcarbonylamino,1,3-thiazol-2-ylcarbonylamino, 1,3-thiazol-4-ylcarbonylamino,1,3-thiazol-5-ylcarbonylamino, 1,2,3-triazol-4-ylcarbonylamino,1,2,3-triazol-5-ylcarbonylamino, 1,2,3-oxadiazol-4-ylcarbonylamino,1,2,3-oxadiazol-5-ylcarbonylamino, 1,2,4-triazol-3-ylcarbonylamino,1,3,4-oxadiazol-3-ylcarbonylamino, tetrazol-5-ylcarbonylamino,pyridin-2-ylcarbonylamino, pyridin-3-ylcarbonylamino,pyridin-4-ylcarbonylamino, pyridazin-3-ylcarbonylamino,pyridazin-4-ylcarbonylamino, pyrimidin-2-ylcarbonylamino,pyrimidin-4-ylcarbonylamino, pyrazin-2-ylcarbonyl-amino,1,2,4-triazin-3-ylcarbonylamino, 1,2,4-triazin-5-ylcarbonylamino,1,2,4-triazin-6-ylcarbonylamino, 1,3,5-triazin-2-ylcarbonylamino, etc.In addition, specific examples in the case where Ra and Rb of Ra(Rb)N—are bonded to form a heterocyclyl include azetidin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, 2-oxoazetidin-1-yl,2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 2-oxoazepan-1-yl, etc. It isnatural that the above specific examples include those to whichtert-butoxycarbonyl or benzyloxy-carbonyl is bonded as a protectivegroup.

Among specific examples of C₁₋₆ alkoxy exemplified by specific examplesof the above ReO—, and RcO— to be obtained from heterocyclyl, preferredare methoxy, ethoxy, propoxy, isopropoxy, cyclobutylmethoxy,azetidin-3-yloxy, oxetan-3-yloxy, thietan-3-yloxy, pyrrolidin-3-yloxy,tetrahydrofuran-3-yloxy, tetrahydrothiophen-3-yloxy,pyrazolidin-4-yloxy, piperidin-3-yloxy, piperidin-4-yloxy,tetrahydro-2H-pyran-3-yloxy, tetrahydro-2H-pyran-4-yloxy,tetrahydro-2H-thiopyran-3-yloxy, tetrahydro-2H-thiopyran-4-yloxy,hexahydropyridazin-4-yloxy, 1,2-oxazolidin-4-yloxy,1,2-oxazinan-4-yloxy, 1,2-oxazinan-5-yloxy, 1,2-thiazinan-4-yloxy,1,2-thiazinan-5-yloxy, azepan-3-yloxy, azepan-4-yloxy, oxepan-3-yloxy,oxepan-4-yloxy, thiepan-3-yloxy, thiepan-4-yloxy, 1,4-diazepan-6-yloxy,1,4-oxazepan-6-yloxy, 1,4-thiazepan-6-yloxy, etc. In addition, inRcO—B—, specific examples of heterocyclyl formed by the bonding of ringRc and B include 1,2-oxazolidine, 1,2-oxazinane, 1,2-oxazepane, etc. Itis natural that the specific examples include those to whichtert-butoxycarbonyl or benzyloxycarbonyl is bonded as a protectivegroup.

In the following, specific examples in the case where C₁₋₆ alkyl, acyl,or heterocyclyl which form the above Ra(Rb)N— or RcO— is modified byC₁₋₆ alkyl, O═, Rg-(CH₂)₀₋₃—, heterocyclyl, phenyl, heteroaryl, acyl,RdO₂S—, Re(Rf)N—, Re(Rf)NCO—, ReO— and ReOCO—, which are defined by Fn1,or by a protective group will be described in detail by way ofrepresentative examples, but it is natural that the examples are notlimited to the scope of the specific examples which are illustrated.

Specific example of C₁₋₆ alkyl modified by amino (H₂N—) which is arepresentative example of Re(Rf)N— include 2-aminoethyl, 2-aminopropyl,3-aminopropyl, 2-amino-1-methylethyl, 2-aminobutyl, 3-aminobutyl,4-aminobutyl, 2-amino-1,1-dimethylethyl, 2-amino-1-methylpropyl,3-amino-2-methylpropyl, etc. It is natural that those to which aprotective tert-butoxycarbonyl or benzyloxycarbonyl which is included inReOCO— is bonded is included in the above specific examples.

In addition, CH₂ to which amino is bonded in 2-aminoethyl in the abovespecific examples is modified by O═ (oxo) to obtain anaminocarbonylalkyl derivative included in Re(RONCO— include2-(amino)-2-oxoethyl, 2-(methylamino)-2-oxoethyl,2-(ethylamino)-2-oxoethyl, 2-oxo-2-(propylamino)ethyl,2-(isopropylamino)-2-oxoethyl, 2-(tert-butylamino)-2-oxoethyl,2-(isobutylamino)-2-oxoethyl, etc.

In addition, specific examples in which the above 2-aminoethylderivative is modified by methylsulfonyl as a representative example ofRdO₂S—, acetyl as a representative example of acyl or carbamoyl (H₂NCO—)as a representative example of Re(RONCO— include2-(methylsulfonylamino)ethyl, 2-(methylsulfonylamino)propyl,3-(methylsulfonylamino)propyl, 2-(methylsulfonylamino)-1-methylethyl,2-(methyl-sulfonylamino)butyl, 3-(methylsulfonylamino)butyl,4-(methylsulfonylamino)butyl, 2-(methylsulfonylamino)-1,1-dimethylethyl,2-(methylsulfonylamino)-1-methylpropyl,3-(methylsulfonylamino)-2-methylpropyl, 2-(acetylamino)ethyl,2-(acetylamino)propyl, 3-(acetylamino)propyl,2-(acetylamino)-1-methylethyl, 2-(acetylamino)butyl,3-(acetylamino)butyl, 4-(acetylamino)butyl,2-(acetylamino)-1,1-dimethylethyl, 2-(acetylamino)-1-methylpropyl,3-(acetylamino)-2-methylpropyl, 2-(carbamoylamino)-ethyl,2-(carbamoylamino)propyl, 3-(carbamoylamino)propyl,2-(carbamoylamino)-1-methylethyl, 2-(carbamoylamino)butyl,3-(carbamoylamino)butyl, 4-(carbamoylamino)-butyl,2-(carbamoylamino)-1,1-dimethylethyl, 2-(carbamoylamino)-1-methylpropyl,3-(carbamoylamino)-2-methylpropyl, etc.

Specific examples in which C₁₋₆ alkyl is modified by hydroxy (HO—) as arepresentative example of ReO— include 2-hydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl, 2-hydroxy-1-methylethyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl,2-hydroxy-1-methylpropyl, 3-hydroxy-2-methylpropyl, etc. It is naturalthat the above specific examples include those in which hydroxy isprotected by triisopropylsilyl included in trialkylsilyl.

Specific example in the case where ethyl as a representative example ofC₁₋₆ alkyl is modified by methylsulfonyl as the representative exampleof RdO₂S— includes 2-(methylsulfonyl)ethyl.

Specific examples of C₁₋₆ alkylcarbonyl, phenylacetyl or benzoylmodified by amino (H₂N—) as the representative example of Re(Rf)N—include 2-aminoacetyl, 2-aminopropanoyl, 3-aminopropanoyl,2-aminobutanoyl, 3-aminobutanoyl, 4-amino-butanoyl,3-amino-2-methylpropanoyl, 2-(2-aminophenyl)acetyl,2-(3-aminophenyl)-acetyl, 2-(4-aminophenyl)acetyl,2-[2-(aminomethyl)phenyl]acetyl, 2-[3-(amino-methyl)phenyl]acetyl,2-[4-(aminomethyl)phenyl]acetyl, 2-aminobenzoyl, 3-amino-benzoyl,4-aminobenzoyl, 2-(aminomethyl)benzoyl, 3-(aminomethyl)benzoyl,4-(aminomethyl)benzoyl, etc. It is natural that those to whichtert-butoxycarbonyl or benzyloxycarbonyl is bonded as a protective groupare included as specific example.

Specific examples of C₁₋₆ alkylcarbonyl, phenylacetyl, benzoyl modifiedby hydroxyl (HO—) as the representative example of ReO— include2-hydroxyacetyl, 2-hydroxypropanoyl, 3-hydroxypropanoyl,2-hydroxybutanoyl, 3-hydroxybutanoyl, 4-hydroxybutanoyl,3-hydroxy-2-methylpropanoyl, 2-(2-hydroxyphenyl)acetyl,2-(3-hydroxyphenyl)acetyl, 2-(4-hydroxyphenyl)acetyl, 2-hydroxybenzoyl,3-hydroxy-benzoyl, 4-hydroxybenzoyl, etc. It is natural that those inwhich hydroxy is protected by triisopropylsilyl included intrialkylsilyl are included in the above specific examples.

Specific examples in which methyl or ethyl as the representative exampleof C₁₋₆ alkyl is modified by heterocyclyl include azetidin-2-ylmethyl,azetidin-3-ylmethyl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl,tetrahydrofuran-3-ylmethyl, tetrahydro-thiophen-3-ylmethyl,pyrazolidin-4-ylmethyl, 1,2-oxazolidin-3-ylmethyl, piperidin-2-ylmethyl,piperidin-3-ylmethyl, piperidin-4-ylmethyl,tetrahydro-2H-pyran-4-ylmethyl, tetrahydro-2H-thiopyran-4-ylmethyl,hexahydropyridazin-4-ylmethyl, piperazin-2-ylmethyl,1,2-oxazinan-3-ylmethyl, morpholin-2-ylmethyl, morpholin-3-ylmethyl,thiomorpholin-2-ylmethyl, thiomorpholin-3-ylmethyl, azepan-2-ylmethyl,azepan-4-ylmethyl, oxepan-2-ylmethyl, oxepan-4-ylmethyl,1,4-diazepan-2-ylmethyl, 1,4-diazepan-6-ylmethyl,2-(azetidin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl,2-(pyrazolidin-1-yl)ethyl, 2-(piperidin-1-yl)ethyl,2-(hexahydropyridazin-1-yl)ethyl, 2-(piperazin-1-yl)ethyl,2-(morpholin-4-yl)ethyl, 2-(thiomorpholin-4-yl)ethyl,2-(1,2-oxazolidin-2-yl)ethyl, 2-(1,2-oxazinan-2-yl)ethyl,2-(azepan-1-yl)ethyl, 2-(1,4-diazepan-1-yl)ethyl, etc. It is naturalthat the above specific examples include those to whichtert-butoxycarbonyl or benzyloxycarbonyl is bonded as a protectivegroup.

In addition, specific examples in which ethyl of the aboveheterocyclyl-ethyl derivative is further modified by O═(oxo) to formaminocarbonyl included in Re(Rf)NCO— include2-(azetidin-1-yl)-2-oxoethyl, 2-oxo-(pyrrolidin-1-yl)ethyl,2-oxo-(pyrazolidin-1-yl)ethyl, 2-oxo-(piperidin-1-yl)ethyl,2-(hexahydropyridazin-1-yl)-2-oxoethyl, 2-oxo-(piperazin-1-yl)ethyl,2-(morpholin-4-yl)-2-oxoethyl, 2-oxo-(thiomorpholin-4-yl)ethyl,2-(1,2-oxazolidin-2-yl)-2-oxoethyl, 2-(1,2-oxazinan-2-yl)-2-oxoethyl,2-(azepan-1-yl)-2-oxoethyl, 2-(1,4-diazepan-1-yl)-2-oxoethyl, etc. It isnatural that the above specific examples include those to whichtert-butoxycarbonyl or benzyloxycarbonyl is bonded as a protectivegroup.

Specific examples in which, among Re(Rf)NCO—, Re and Rf modified by Fn1are bonded to form a heterocyclyl include azetidin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl, 1,2-oxazolidin-2-ylcarbonyl,pyrazolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,hexahydropyridazin-1-ylcarbonyl, piperazin-1-ylcarbonyl,morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl,1,2-oxazinan-2-ylcarbonyl, azepan-1-ylcarbonyl,1,4-diazepan-1-ylcarbonyl, etc.

Specific examples in the case where methyl or ethyl as therepresentative example of C₁₋₆ alkyl is modified by heteroaryl includepyrrol-2-ylmethyl, furan-2-ylmethyl, pyrazol-3-ylmethyl,pyrazol-4-ylmethyl, imidazol-2-ylmethyl, imidazol-4-ylmethyl,1,2-oxazol-3-ylmethyl, 1,3-oxazol-2-ylmethyl, 1,3-oxazol-4-ylmethyl,1,3-thiazol-2-ylmethyl, 1,3-thiazol-4-ylmethyl,1,2,3-triazol-4-ylmethyl, 1,2,3-oxadiazol-4-ylmethyl,1,2,4-triazol-3-ylmethyl, 1,3,4-oxadiazol-2-ylmethyl,tetrazol-5-ylmethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl,pyridin-4-ylmethyl, pyridazin-3-ylmethyl, pyridazin-4-ylmethyl,pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, pyrazin-2-ylmethyl,1,2,4-triazin-3-ylmethyl, 1,2,4-triazin-5-ylmethyl,1,3,5-triazin-2-ylmethyl, 2-(pyrrol-1-yl)ethyl, 2-(pyrazol-1-yl)ethyl,2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl,2-(1,2,4-triazol-4-yl)ethyl, 2-(tetrazol-1-yl)ethyl, etc. It is naturalthat the above specific examples include those to whichtert-butoxycarbonyl or benzyloxycarbonyl is bonded as a protectivegroup.

Specific examples in which heterocyclyl is modified by methyl as therepresentative example of C₁₋₆ alkyl include 1-methylazetidine,3-methylazetidine, 1-methylpyrrolidine, 3-methylpyrrolidine,1-methylimidazolidine, 3-methyloxazolidine, 1-methylpyrazolidine,1-methylpiperidine, 4-methylpiperidine, 2-methyltetrahydro-2H-pyran,4-methyltetrahydro-2H-pyran, 1-methylpiperazine, 1,4-dimethylpiperazine,4-methylmorpholine, 4-methyl-thiomorpholine, 1-methylazepane,1-methyl-1,4-diazepane, 1,4-dimethyl-1,4-diazepane, etc. It is naturalthat the above specific examples include those to whichtert-butoxycarbonyl or benzyloxycarbonyl is bonded as a protectivegroup.

Specific examples of heterocyclyl modified by O═ (oxo) include2-oxoazetidine, 2-oxopyrrolidine, 3-oxopyrazolidine, 2-oxoimidazolidine,3-oxo-1,2-oxazolidine, 2-oxooxazolidine, 2-oxopiperidine,3-oxo-hexahydropyridazine, 2-oxopiperazine, 3-oxomorpholine,3-oxo-1,2-oxazinane, 2-oxoazepane, 2-oxo-1,4-diazepane,5-oxo-1,4-diazepane, etc.

Specific examples in the case where ethyl as the representative exampleof C₁₋₆ alkyl described above is modified by heterocyclyl and furtherheterocyclyl is modified by O═ (oxo) include2-(2-oxoazetidin-1-yl)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl,2-(2-oxoimidazolidin-3-yl)ethyl, 2-(2-oxooxazolidin-3-yl)ethyl,2-(3-oxopyrazolidin-1-yl)ethyl, 2-(2-oxopiperidin-1-yl)ethyl,2-(3-oxo-hexahydropyridazin-1-yl)ethyl, 2-(2-oxopiperazin-1-yl)ethyl,2-(3-oxomorpholin-4-yl)ethyl, 2-(3-oxo-1,2-oxazolidin-2-yl)ethyl,2-(3-oxo-1,2-oxazinan-2-yl)ethyl, 2-(2-oxoazepan-1-yl)ethyl,2-(2-oxo-1,4-diazepan-1-yl)ethyl, 2-(5-oxo-1,4-diazepan-1-yl)ethyl, etc.

Specific examples of the heterocyclylcarbonyl in which the heterocyclylis modified by O═ (oxo) include 4-oxoazetidin-2-ylcarbonyl,5-oxopyrrolidin-2-ylcarbonyl, 2-oxoimidazolidin-4-ylcarbonyl,2-oxooxazolidin-4-ylcarbonyl, 5-oxopyrazolidin-3-ylcarbonyl,6-oxopiperidin-2-ylmethyl, 2-oxopiperidin-4-ylcarbonyl,6-oxo-hexahydropyridazin-3-ylcarbonyl,3-oxo-hexahydropyridazin-4-ylcarbonyl, 5-oxopiperazin-2-ylcarbonyl,6-oxopiperazin-2-ylcarbonyl, 5-oxomorpholin-2-ylcarbonyl,5-oxomorpholin-3-ylcarbonyl, 3-oxothiomorpholin-2-ylcarbonyl,5-oxothiomorpholin-3-ylcarbonyl, 7-oxoazepan-2-ylcarbonyl,2-oxoazepan-4-ylcarbonyl, 7-oxo-1,4-diazepan-2-ylcarbonyl,2-oxo-1,4-diazepan-6-ylcarbonyl, etc. It is natural that the abovespecific examples include those to which tert-butoxycarbonyl orbenzyloxycarbonyl is bonded as protective group.

Specific examples of heterocyclyl modified by amino (H₂N—) as therepresentative example of Re(Rf)N— include a group derived from3-aminoazetidine, 3-aminopyrrolidine, 3-amino-tetrahydrofuran,3-amino-tetrahydrothiophene, 4-aminopyrazolidine, 4-aminopiperidine,4-amino-tetrahydro-2H-pyran, 4-amino-tetrahydro-2H-thiopyran,4-amino-hexahydropyridazine, 4-amino-1,2-oxazolidine,4-amino-1,2-oxazinane, 4-aminoazepane, 4-aminooxepane,6-amino-1,4-diazepane, etc. It is natural that the above specificexamples include those to which tert-butoxycarbonyl or benzyloxycarbonylis bonded as a protective group.

Specific examples of heterocyclyl modified by hydroxy (HO—) as therepresentative example of ReO— include a group derived from3-hydroxyazetidine, 3-hydroxypyrrolidine, 4-hydroxypyrazolidine,4-hydroxytetrahydrofuran, 4-hydroxytetrahydrothiophene,3-hydroxypiperidine, 4-hydroxypiperidine,4-hydroxytetrahydro-2H-thiopyran, 4-hydroxy-hexahydropyridazine,4-hydroxy-1,2-oxazolidine, 4-hydroxy-1,2-oxazinane, 4-hydroxyazepane,6-hydroxy-1,4-diazepane, etc. It is natural that the above specificexamples include those in which hydroxy is protected bytriisopropylsilyl, heterocyclyl is protected by tert-butoxycarbonyl orbenzyloxycarbonyl.

Specific examples of heteroaryl modified by methyl as the representativeexample of C₁₋₆ alkyl include a group derived from 1-methylpyrrole,2-methylpyrrole, 3-methylpyrrole, 1-methylpyrazole, 3-methylpyrazole,4-methylpyrazole, 2-methylimidazole, 4-methylimidazole,4-methyl-1,2-oxazole, 5-methyl-1,2-oxazole, 2-methyl-1,3-oxazole,4-methyl-1,3-oxazole, 5-methyl-1,3-oxazole, 1-methyl-1,2,3-triazole,4-methyl-1,2,3-triazole, 1-methyl-1,2,4-triazole,3-methyl-1,2,4-triazole, 1-methyltetrazole, 5-methyltetrazole,2-methyl-1,3,4-oxadiazole, 2-methylpyridine, 3-methylpyridine,4-methylpyridine, 3-methylpyridazine, 4-methylpyridazine,2-methylpyrimidine, 4-methylpyrimidine, 2-methylpyrazine,3-methyl-1,2,4-triazine, 5-methyl-1,2,4-triazine,6-methyl-1,2,4-triazine, 2-methyl-1,3,5-triazine, etc. It is naturalthat the specific examples include those to which tert-butoxycarbonyl orbenzyloxycarbonyl is bonded as a protective group.

Specific examples of heteroaryl modified by amino (H₂N—) as therepresentative example of Re(Rf)N— include a group derived from2-aminopyrrole, 3-aminopyrrole, 2-aminofuran, 3-aminofuran,3-aminopyrazole, 4-aminopyrazole, 2-aminoimidazole, 3-amino-1,2-oxazole,2-amino-1,3-oxazole, 2-aminothiazole, 4-amino-1,2,3-triazole,3-amino-1,2,4-triazole, 2-amino-1,3,4-thiadiazole, 5-aminotetrazole,2-amino-1,3,4-oxadiazole, 2-aminopyridine, 3-aminopyridazine,2-aminopyrimidine, 3-amino-1,2,4-triazine, 2-amino-1,3,5-triazine, etc.It is natural that the specific examples include those to whichtert-butoxycarbonyl or benzyloxycarbonyl is bonded as a protectivegroup.

Specific examples of heteroaryl modified by hydroxy (OH—) as therepresentative example of ReO— include a group derived from2-hydroxypyrrole, 3-hydroxypyrrole, 2-hydroxyfuran, 3-hydroxyfuran,3-hydroxypyrazole, 4-hydroxypyrazole, 2-hydroxyimidazole,3-hydroxy-1,2-oxazole, 2-hydroxy-1,3-oxazole, 2-hydroxythiazole,4-hydroxy-1,2,3-triazole, 3-hydroxy-1,2,4-triazole, 5-hydroxytetrazole,2-hydroxy-1,3,4-oxadiazole, 2-hydroxypyridine, 3-hydroxypyridazine,2-hydroxypyrimidine, 3-hydroxy-1,2,4-triazine, 2-hydroxy-1,3,5-triazine,etc. It is natural that the specific examples include those in whichhydroxy is protected by triisopropylsilyl, and heteroaryl is protectedby tert-butoxycarbonyl or benzyloxycarbonyl.

As the specific examples of Ra(Rb)N— comprising the above C₁₋₆ alkyl oracyl, preferred are amino, methylamino, ethylamino, propylamino,isopropylamino, dimethylamino, diethylamino, phenylamino, acetylamino,propanoylamino, butanoylamino, 2-methylpropanoylamino,2,2-dimethylpropanoylamino, 2-aminoacetylamino, 3-aminopropanoylamino,2-methoxyacetylamino, phenylacetylamino, 2-(4-aminophenyl)acetylamino,2-(4-aminomethylphenyl)acetylamino, benzoylamino, 4-aminobenzoylamino,4-aminomethylbenzoylamino, [(azetidin-2-yl)carbonyl]amino,[(pyrrolidin-2-yl)carbonyl]amino, [(pyrrolidin-3-yl)carbonyl]amino,[(piperidin-2-yl)carbonyl]amino, [(piperidin-3-yl)carbonyl]amino,[(piperidin-4-yl)carbonyl]amino,[(4-cyclopentylmethylpiperidin-2-yl)carbonyl]amino,[(tetrahydro-2H-pyran-4-yl)carbonyl]amino,[(5-oxopyrrolidin-2-yl)carbonyl]amino, furan-2-ylcarbonylamino,1,3-oxazol-4-ylcarbonylamino, pyridin-2-ylcarbonylamino,pyridin-3-ylcarbonylamino, pyridin-4-ylcarbonylamino,methanesulfonylamino, dimethylaminocarbonylamino,diethylaminocarbonylamino, phenylaminocarbonylamino,morpholin-4-ylcarbonylamino, methoxycarbonylamino, ethoxycarbonylamino,tert-butoxycarbonylamino, etc. In addition, specific examples in thecase where among Ra(Rb)N—, Ra and Rb modified by Fn1 are bonded to forma heterocyclyl include azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, azepan-1-yl,1,4-diazepan-1-yl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl,2-oxopiperidin-1-yl, 2-oxo-piperazin-1-yl, 3-oxo-morpholin-4-yl,2-oxoazepan-1-yl, 2-oxo-1,4-diazepan-1-yl, etc. It is natural that freeNH or HO modified by a protective group such as tert-butoxycarbonyl,benzyloxycarbonyl, or triisopropylsilyl is included in the aboveRa(Rb)N—, if necessary.

In addition, specific examples of RcO— comprising the above C₁₋₆ alkoxyand heterocyclyloxy include preferably methoxy, ethoxy, propoxy,isopropoxy, cyclobutylmethoxy, azetidin-3-yloxy, pyrrolidin-3-yloxy,tetrahydrofuran-3-yloxy, tetrahydrothiophen-3-yloxy,pyrazolidin-4-yloxy, piperidin-3-yloxy, piperidin-4-yloxy,tetrahydro-2H-pyran-4-yloxy, tetrahydro-2H-thiopyran-4-yloxy,1,2-oxazolidin-4-yloxy, 1,2-oxazinan-4-yloxy, 1,2-oxazinan-5-yloxy,azepan-3-yloxy, azepan-4-yloxy, 1,4-diazepan-6-yloxy,1,4-oxazepane-6-yloxy, 2-aminoethoxy, 2-(methylamino)ethoxy,2-(propylamino)ethoxy, 2-(isopropylamino)ethoxy,2-(dimethylamino)ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy,2-aminopropoxy, 3-aminopropoxy, 2-amino-1-methylethoxy,2-amino-2-oxo-ethoxy, 2-(dimethylamino)-2-oxo-ethoxy,2-(methylsulfonyl)ethoxy, (azetidin-2-yl)methoxy,(azetidin-3-yl)methoxy, (pyrrolidin-2-yl)methoxy,(pyrrolidin-3-yl)methoxy, (piperidin-2-yl)methoxy,(piperidin-3-yl)methoxy, (piperidin-4-yl)methoxy,(4-oxoazetidin-2-yl)methoxy, (5-oxopyrrolidin-2-yl)methoxy,(6-oxopiperidin-2-yl)methoxy, 2-(azetidin-1-yl)ethoxy,2-(pyrrolidin-1-yl)ethoxy, 2-(piperidin-1-yl)ethoxy,2-(morpholin-4-yl)ethoxy, 2-(piperazin-1-yl)ethoxy,2-(1,4-diazepan-1-yl)ethoxy, 2-(azetidin-1-yl)-2-oxoethoxy,2-oxo-2-(pyrrolidin-1-yl)ethoxy, 2-oxo-2-(piperidin-1-yl)ethoxy,2-oxo-2-(piperazin-1-yl)ethoxy, 2-(morpholin-4-yl)-2-oxoethoxy,2-(1,4-diazepan-1-yl)-2-oxoethoxy, 2-(2-oxoazetidin-1-yl)ethoxy,2-(2-oxopyrrolidin-1-yl)ethoxy, 2-(2-oxopiperidin-1-yl)ethoxy,2-(2-oxoimidazolidin-1-yl)ethoxy, 2-(2-oxo-1,3-oxazolidin-3-yl)ethoxy,2-(pyrrol-1-yl)ethoxy, 2-(imidazol-1-yl)ethoxy,2-(2-sulfonate-1H-imidazol-1-ium-1-yl)ethoxy. In addition, specificexamples of heterocyclyl formed by bondage of Rc and B or Rc and Bmodified by Fn1 in RcO-B— include 1,2-oxazolidin-2-yl,1,2-oxazinan-2-yl, 1,2-oxazepan-2-yl, 1,2,5-oxadiazepan-2-yl,1,5,2-dioxazepan-5-yl, etc. It is natural that free NH or HO modified bya protective group such as tert-butoxycarbonyl, benzyloxycarbonyl, ortriisopropylsilyl is included in the above RcO—, if necessary.

More specific examples of compounds provided by the present inventionpreferably include compounds as follows:

-   (2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxylate,-   tert-butyl    2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxylate,-   tetrabutylammonium tert-butyl    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-oct-2-yl]carbonyl}hydrazinecarboxylate,-   sodium tert-butyl    1-methyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,-   tert-butyl    2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate,-   tert-butyl    2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate,-   pyridinium tert-butyl    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate,-   (2S,5R)—N′-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   sodium    (2S,5R)—N′,N′-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-N′,N′-dimethyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′,N′-dimethyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′,N′-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   sodium    (2S,5R)—N′-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-acetyl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-acetyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tetrabutylammonium    (2S,5R)—N′-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   sodium    (2S,5R)-7-oxo-N′-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-hydroxy-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)-7-oxo-N′-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   sodium    (2S,5R)—N′-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-hydroxy-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   sodium    (2S,5R)—N′-(2,2-dimethylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-N′-(2,2-dimethylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-(2,2-dimethylpropanoyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-(2,2-dimethylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   sodium    (2S,5R)—N′-acetyl-N′-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-acetyl-6-benzyloxy-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-acetyl-6-hydroxy-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-acetyl-N′-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   (2S,5R)—N′-(aminoacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    [2-(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamate,-   tert-butyl    [2-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinyl)-2-oxoethyl]carbamate,-   pyridinium tert-butyl    [2-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamate,-   (2S,5R)—N′-(3-aminopropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    [3-(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate,-   tert-butyl    [3-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinyl)-3-oxopropyl]carbamate,-   pyridinium tert-butyl    [3-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate,-   (2S,5R)—N′-[(4-aminophenyl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    {4-[2-(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate,-   tert-butyl    {4-[2-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate,-   tetrabutylammonium tert-butyl    {4-[2-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate,-   sodium    (2S,5R)—N′-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-N′-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,    (2S,5R)-6-hydroxy-N′-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   sodium    (2S,5R)—N′-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-benzoyl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-benzoyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-(4-aminobenzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    {4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate,-   tert-butyl    {4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate,-   tetrabutylammonium tert-butyl    {4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate,-   (2S,5R)—N′-(4-(aminomethyl)benzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   tert-butyl    {4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate,-   tert-butyl    {4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate,-   pyridinium tert-butyl    {4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate,-   sodium    (2S,5R)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-7-oxo-N-(2-oxopyrrolidin-1-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-hydroxy-7-oxo-N-(2-oxopyrrolidin-1-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   sodium    (2S,5R)-7-oxo-6-(sulfooxy)-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-7-oxo-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-hydroxy-7-oxo-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)-7-oxo-6-(sulfooxy)-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-7-oxo-N′-(piperidin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   tert-butyl    4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinyl)carbonyl]piperidine-1-carboxylate,-   pyridinium tert-butyl    4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   (2S,5R)-7-oxo-N′-[(2S)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   tert-butyl    (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   tert-butyl    (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   (2S,5R)-7-oxo-N′-[(2R)-piperidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   tert-butyl    (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   tert-butyl    (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   (2S,5R)-7-oxo-N′-[(2S)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   tert-butyl    (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,-   tert-butyl    (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,-   (2S,5R)-7-oxo-N′-[(2R)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   tert-butyl    (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,-   tert-butyl    (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate,-   (2S,5R)—N′-{[(2S,4R)-4-cyclopropylmethylpiperidin-2-yl]carbonyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    (2S,4R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-4-cyclopropylmethylpiperidine-1-carboxylate,-   tert-butyl    (2S,4R)-4-cyclopropylmethyl-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2S,4R)-4-cyclopropylmethyl-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate,-   sodium    (2S,5R)-7-oxo-N′-{[(2S)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    (2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,-   tert-butyl    (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,-   sodium    (2S,5R)-7-oxo-N′-{[(2R)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   tert-butyl    (2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,-   tert-butyl    (2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate,-   sodium    (2S,5R)—N′-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-N′-(furan-2-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)—N′-(furan-2-ylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   sodium    (2S,5R)—N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   (2S,5R)-6-hydroxy-N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   sodium    (2S,5R)-7-oxo-N′-(pyridin-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-7-oxo-N′-(pyridin-3-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-hydroxy-7-oxo-N′-(pyridin-3-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)-7-oxo-N′-(pyridin-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   sodium    (2S,5R)-7-oxo-N′-(pyridin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-7-oxo-N′-(pyridin-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-hydroxy-7-oxo-N′-(pyridin-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)-7-oxo-N′-(pyridin-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   sodium    N,N-dimethyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide,-   2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide,-   2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide,-   pyridinium    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide,-   sodium    N,N-diethyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxamide,-   2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-diethylhydrazinecarboxamide,-   N,N-diethyl-2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxamide,-   pyridinium    N,N-diethyl-2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide,-   sodium    2-{[(R2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide,-   2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide,-   2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenyl-hydrazinecarboxamide,-   pyridinium    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide,-   sodium    (2S,5R)—N′-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-N′-(morpholin-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   (2S,5R)-6-hydroxy-N′-(morpholin-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carbohydrazide,-   sodium methyl    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,-   methyl    2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxylate,-   methyl    2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxylate,-   tetrabutylammonium methyl    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,-   sodium ethyl    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,-   ethyl    2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxylate,-   ethyl    2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxylate,-   pyridinium ethyl    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,-   sodium tert-butyl    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,-   tert-butyl    2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,-   tert-butyl    2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-hydrazinecarboxylate,-   pyridinium tert-butyl    2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate,-   sodium    (2S,5R)—N′-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-benzyloxy-N′-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   (2S,5R)-6-hydroxy-N′-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide,-   pyridinium    (2S,5R)—N′-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbohydrazide,-   sodium    (2S,5R)—N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-hydroxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   sodium    (2S,5R)—N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-hydroxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tetrabutylammonium    (2S,5R)—N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   sodium    (2S,5R)—N-ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-ethoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-ethoxy-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   sodium    (2S,5R)—N-(cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-(cyclobutylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-(cyclobutylmethoxy)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-(cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}carbamate,-   tert-butyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}carbamate,-   tetrabutylammonium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,-   pyridinium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,-   sodium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,-   (2S,5R)—N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate,-   tert-butyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}methylcarbamate,-   tetrabutylammonium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate,-   (2S,5R)—N-[2-(ethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}ethylcarbamate,-   tert-butyl ethyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,-   tetrabutylammonium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}ethylcarbamate,-   (2S,5R)-7-oxo-N-[2-(propylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propylcarbamate,-   tert-butyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}propylcarbamate,-   tetrabutylammonium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propylcarbamate,-   (2S,5R)-7-oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate,-   tert-butyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}propan-2-ylcarbamate,-   tetrabutylammonium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate,-   (2S,5R)—N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-[2-(dimethylamino)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-[2-(dimethylamino)ethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-{[(2S)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    {(2S)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   tert-butyl    {(2S)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   tetrabutylammonium tert-butyl    {(2S)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   (2S,5R)—N-{[(2R)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    {(2R)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   tert-butyl    {(2R)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}-   carbamate, tetrabutylammonium tert-butyl    {(2R)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   (2S,5R)—N-{[(2S)-1-aminopropan-2-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   tert-butyl    {(2S)-2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,-   tert-butyl    {(2S)-2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,-   tetrabutylammonium tert-butyl    {(2S)-2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,-   (2S,5R)—N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    {3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,-   tert-butyl    {3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]propyl}carbamate,-   tetrabutylammonium tert-butyl    {3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,-   sodium    (2S,5R)-2-(1,2-oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octan-7-one,-   (2S,5R)-6-benzyloxy-2-(1,2-oxazolidin-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one,-   (2S,5R)-6-hydroxy-2-(1,2-oxazolidin-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one,-   pyridinium    (2S,5R)-2-(1,2-oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octan-7-one,-   sodium    (2S,5R)-2-(1,2-oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octan-7-one,-   (2S,5R)-6-benzyloxy-2-(1,2-oxazinan-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one,-   (2S,5R)-6-hydroxy-2-(1,2-oxazinan-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octan-7-one,-   pyridinium    (2S,5R)-2-(1,2-oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one,-   sodium    (2S,5R)—N-[2-(morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-hydroxy-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-[2-(morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[2-(piperazin-1    -yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    4-{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate,-   tert-butyl    4-{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}piperazine-1-carboxylate,-   tetrabutylammonium tert-butyl    4-{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate,-   (2S,5R)-7-oxo-N-[2-(1,4-diazepan-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    4-{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepane-1-carboxylate,-   tert-butyl    4-{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}-1,4-diazepane-1-carboxylate,-   pyridinium tert-butyl    4-{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepane-1-carboxylate,-   (2S,5R)—N-[(2S)-azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   (2S,5R)-7-oxo-N-[(2S)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   pyridinium tert-butyl    (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   (2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    (2R)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   tert-butyl    (2R)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2R)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   (2S,5R)-7-oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   (2S,5R)—N-(azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate,-   tert-butyl    3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]azetidine-1-carboxylate,-   tetrabutylammonium tert-butyl    3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate,-   (2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    (3R)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   tert-butyl    (3R)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (3R)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   (2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    (3S)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   tert-butyl    (3S)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl (3S)-3    -[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   (2S,5R)—N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   tert-butyl    3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   tetrabutylammonium tert-butyl    3-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1    -carboxylate,-   (2S,5R)-7-oxo-N-[(3R)-piperidin-3    -ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    (3R)-3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   tert-butyl    (3R)-3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (3R)-3-({[({[2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   (2S,5R)-7-oxo-N-(piperidin-4-yloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    4-[([{(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate,-   tert-butyl    4-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate,-   tetrabutylammonium tert-butyl    4-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate,-   (2S,5R)-7-oxo-N-(piperidin-4-ylmethoxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   tert-butyl    4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]methyl}piperidine-1-carboxylate,-   tetrabutylammonium tert-butyl    4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   sodium    (2S,5R)—N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-hydroxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   pyridinium (2S,5R)—N-[2-(1H-imidazol-1    -yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide,-   sodium (2S,5R)-7-oxo-N-[2-(1H-pyrrol-1    -yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-hydroxy-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium (2S,5R)-7-oxo-N-[2-(1H-pyrrol-1    -yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   disodium    1-{2-[({[(2S,5R)-7-oxo-6-(sulfonateoxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1H-imidazole-2-sulfonate,-   (2S,5R)-6-benzyloxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-hydroxy-N-[2-(1H-imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   pyridinium    1-{2-[({[(2S,5R)-7-oxo-6-(sulfonateoxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1H-imidazole-1-ium-2-sulfonate,-   sodium    (2S,5R)—N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-[2-(dimethylamino)-2-oxoethoxy]-6-hydroxy    -7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   pyridinium    (2S,5R)—N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[2-oxo-2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]acetyl}piperazine-1-carboxylate,-   tert-butyl    4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]acetyl}piperazine-1-carboxylate,-   tetrabutylammonium tert-butyl    4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylate,-   sodium    (2S,5R)—N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-hydroxy-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-[2-(1,4-diazepan-1-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   tert-butyl    4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]acetyl}-1,4-diazepane-1-carboxylate,-   tert-butyl    4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]acetyl}-1,4-diazepane-1-carboxylate,-   tetrabutylammonium tert-butyl    4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepane-1-carboxylate,-   sodium    (2S,5R)-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-hydroxy-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   pyridinium    (2S,5R)-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide,-   sodium    (2S,5R)-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-hydroxy-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   sodium    (2S,5R)—N-(2-hydroxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-7-oxo-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-hydroxy-7-oxo-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tetrabutylammonium    (2S,5R)-7-oxo-6-(sulfooxy)-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   sodium    (2S,5R)—N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-(2-methoxyethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-hydroxy-N-(2-methoxyethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   sodium    (2S,5R)—N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-[2-(methylsulfonyl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-hydroxy-N-[2-(methylsulfonyl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   benzyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}carbamate,    and-   tert-butyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}carbamate.

Also, as the specific examples of the compounds of the presentinvention, the following compound groups are preferably mentioned.

in the above formulae, P² represents tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), or H; P³ represents benzyl (Bn), H or SO₃M;where M represents H, sodium, pyridinium or tetrabutylammonium.

in the above formulae, P² represents tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), or H; P³ represents benzyl (Bn), H or SO₃M;where M represents H, sodium, pyridinium or tetrabutylammonium, and Msrepresents methylsulfonyl.

in the above formulae, P² represents tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), or H; P³ represents benzyl (Bn), H or SO3M;where M represents H, sodium, pyridinium or tetrabutylammonium.

in the above formulae, P² represents tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), or H; P³ represents benzyl (Bn), H or SO₃M;where M represents H, sodium, pyridinium or tetrabutylammonium; and P⁴represents triisopropylsilyl or H.

More preferably, the specific examples include:

-   tert-butyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}carbamate,-   tert-butyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}carbamate,-   pyridinium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,-   sodium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,-   tetrabutylammonium tert-butyl    {2-[*{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,-   (2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   benzyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}carbamate,-   (2S,5R)—N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate,-   tert-butyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}methylcarbamate,-   tetrabutylammonium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate,-   (2S,5R)-7-oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    {2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate,-   tert-butyl    {2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]ethyl}propan-2-ylcarbamate,-   tetrabutylammonium tert-butyl    {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate,-   (2S,5R)—N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-6-benzyloxy-N-[2-(dimethylamino)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-[2-(dimethylamino)ethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   pyridinium    (2S,5R)—N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-{[(2S)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    {(2S)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   tert-butyl    {(2S)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   tetrabutylammonium tert-butyl    {(2S)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   (2S,5R)—N-{[(2R)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    {(2R)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   tert-butyl    {(2R)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   tetrabutylammonium tert-butyl    {(2R)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate,-   (2S,5R)—N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    {3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]propyl}carbamate,-   tert-butyl    {3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]propyl}carbamate,-   tetrabutylammonium tert-butyl    {3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate,-   (2S,5R)—N-[(2S)-azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   (2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    (2R)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   tert-butyl    (2R)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2R)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate,-   (2S,5R)-7-oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   tert-butyl    (2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate,-   (2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    (3S)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   tert-butyl    (3S)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   tetrabutylammonium tert-butyl    (3S)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate,-   (2S,5R)—N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   tert-butyl    3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,-   tert-butyl    3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-amino)oxy]methyl}azetidine-1-carboxylate,    and-   tetrabutylammonium tert-butyl    3-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo-[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate,    and the following compound group may be mentioned.

in the above formulae, P² represents tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz) or H; P³ represents benzyl (Bn), H or SO₃M;where M represents H, sodium, pyridinium or tetrabutylammonium.

Most preferably,

-   (2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-[2-(methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-[2-(dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-{[(2S)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-{[(2R)-2-aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)—N-(3-aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,-   (2S,5R)—N-[(2S)-azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[(2S)-piperidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide,-   (2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,    and-   (2S,5R)—N-(azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide    are mentioned.

The medicament provided by the present invention comprises a substanceselected from the group consisting of the compound represented by theformula (I), (II) or (III) and a pharmaceutically acceptable saltthereof, and a hydrate thereof or a solvate thereof as an effectiveingredient, is administered orally or parenterally, and preferablyadministered parenterally. The compound of the present invention and aβ-lactam antibiotic can be administered by the method in whichindividually prepared respective medicaments at the time of use areadministered simultaneously or separately in combination, or the methodin which both of the medicaments are previously mixed generally by usingone or more additives (carrier) for preparation to prepare apharmaceutical composition and administering the same.

Specific examples of the pharmaceutical composition for oraladministration may include a tablet, a capsule, a granule, powder, apill, an aqueous or non-aqueous solution for oral administration and asuspension.

As an administration route for the parenteral administration, there maybe mentioned intranasal, eye drops, ear drops, percutaneous,tracheobronchial, endorectal, in urinary organ, subcutaneous,intramuscular and intravenous.

Specific examples of the pharmaceutical composition for the parenteraladministration as an intravenous administration may include an injectionsolution for the intravenous administration in which a powdered form ofthe pharmaceutical composition is dissolved in an acceptable solvent.The acceptable solvent may be mentioned, for example, steric water forinjection, physiological saline solution, glucose liquid, Ringer'ssolution, bacteriostatic water for injection containing methylparabenand propylparaben, or bacteriostatic water for injection containingbenzyl alcohol.

The pharmaceutical composition in the powder form for the parenteraladministration can be manufactured by subjecting to sterilizationprocess the compound of the present invention which is an active bodyand a β-lactam antibiotic, dispensing in a sealed vial and subjecting tolyophilization, or dispensing the pharmaceutical composition in thestate of sterilized powder into a sealed vial. Specific methods for thesterilization process may be preferably mentioned:

a method in which an individual or mixed solution is subjected toremoval of endotoxin, filtration of insoluble matter, then,crystallization, filling in a sealed vial and gamma ray irradiation;

a method in which an individual or mixed solution is subjected toremoval of endotoxin, aseptic filtration, final sterilization such assteam sterilization under pressure and pulsed-light radiation, andlyophilization;

a method in which individual solution is subjected to removal ofendotoxin, aseptic filtration under aseptic atmosphere, successivelyfilling in a sealed vial, freezing and overlaying, and then,lyophilization;

a method in which each solution of the compound is individuallysubjected to removal of endotoxin, aseptic filtration, andcrystallization under aseptic atmosphere;

a method in which either of the medicament in the state of sterilizedpowder crystallized under aseptic atmosphere is overlaid under asepticatmosphere on another medicament in the state of sterilized powder whichhas been lyophilized in a sealed vial; and

a method in which either of the medicament in the state of sterilizedpowder lyophilized and the other medicine in the state of sterilizedpowder crystallized under aseptic atmosphere are mixed under asepticatmosphere.

More preferred are the method in which an individual solution issubjected to removal of endotoxin, aseptic filtration under asepticatmosphere, successively filling in a sealed vial, freezing andoverlaying, and then, lyophilization, or the method in which eachsolution of the compound is individually subjected to removal ofendotoxin, aseptic filtration, and crystallization under asepticatmosphere.

The above-mentioned pharmaceutical composition can be stored at a roomtemperature or lower until it is prepared as an intravenous injectionsolution, and used by dissolving therein at the time of use. Theconcentration of the compound of the present invention in thereconstituted intravenous injection solution is in the range of, forexample, 1 mg/mL to 50 mg/mL.

The administration dose and the number of administration of thepharmaceutical composition of the present invention are not specificallylimited, and the administration dose and the number of administrationcan be optionally determined depending on the various conditions such asthe purpose of the treatment or prophylaxis, kind of the diseases, age,body weight and symptom of the patient. The effective bloodconcentration of the compound of the present invention to be used incombination with the β-lactam antibiotic is so adjusted that itpreferably maintains 1 μg/mL or more during the administration of theβ-lactam antibiotic. The administration dose of the compound accordingto the present invention for intravenous administration is preferably 2to 75 mg/kg per each time, and for oral administration is preferably 4to 300 mg/kg, in several times per day depending on the number ofadministration times of the β-lactam antibiotic, preferably administered2 to 6 times.

Here, the β-lactam antibiotic which can be used in combination with thecompound of the present invention may be mentioned penicillin, cephemand carbapenem.

Specific examples of penicillins include benzylpenicillin,phenethicillin, cloxacillin, dicloxacillin, ampicillin, cyclacillin,amoxycillin, talampicillin, bacampicillin, lenampicillin, aspoxicillin,piperacillin, sulbenicillin, pivmecillinam, sultamicillin,phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin,epicillin, ticarcillin, pirbenicillin, azlocillin, mezlocillin, andother known penicillins

Specific examples of cephems include cefaclor, cefazolin, cefatrizine,cefadroxil, cephapirin, cefamandole nafate, cephradine, cephalexin,cephalothin, cefepime, cefoxitin, cefixime, ceftazidime, cefditoren,cefdinir, cefsulodin, cefoselis, cefozopran, cefotaxime, ceftazidime,ceftaroline, cefotiam, ceftizoxime, ceftibuten, ceftezole, cefteram,ceftriaxone, cefonicid, cefpiramide, cefpirome, cefbuperazone,cefprozil, cefoperazone, cefpodoxime, cefminox, cefmetazole,cefmenoxime, cefradine, cefroxadine, cefuroxime, ceftolozane (CXA101,(6R,7R)-3-[5-amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazole-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamide]-3-cephem-4-carboxylic acid hydrogen sulfate) and other known cephems.

Examples of the carbapenem may be mentioned imipenem, panipenem,meropenem, biapenem, doripenem, ertapenem and tebipenem, and a DHP-1inhibitor such as sodium cilastatin may be used in combination, ifnecessary.

Examples of the β-lactam antibiotics other than the carbapenems,penicillins and cephems may be mentioned a β-lactam antibiotic such asaztreonam, carumonam, latamoxef, flomoxef, loracarbef, faropenem andritipenem.

Examples of the penicillins which are particularly suitable for using incombination with the compound of the present invention may be mentionedampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin,mezlocillin and ticarcillin. Such penicillins may be used, for example,in the form of a pharmaceutically acceptable salt such as a sodium salt.As the other embodiment, ampicillin or amoxicillin can be used incombination with the compound of the formula (I) in the form of asuspension for injection or amphoteric ion type (ampicillin. trihydrateor amoxicillin trihydrate) fine particles for a suspension forinjection.

Particularly suitable cephems for combined administration with thecompound of the present invention are cefotaxime, ceftriaxone,ceftazidime, cefepime, etc., and these can be used in the form of apharmaceutically acceptable salt such as a sodium salt.

Particularly suitable carbapenems for combined administration with thecompound of the present invention are imipenem, meropenem, biapenem,doripenem and ertapenem.

An example of the particularly suitable β-lactam antibiotic for combinedadministration with the compound of the present invention other than thecarbapenems, penicillins and cephems is aztreonam.

By using the compound of the present invention and a β-lactam antibioticin combination, it can be used for the treatment of infectious diseasecaused by class A and class C β-lactamase producing strains, and ESBLand KPC2 carbapenemase producing strains, in addition to bacterialinfection included in the antimicrobial spectrum of the antibiotics.

The class A and class C β-lactamase producing strains, and ESBL and KPC2carbapenemase producing strains include Escherichia coli, Klebsiellapneumoniae, Enterobacter cloacae, Citrobacter freundii, Serratiamarcescens, Morganella morganii, Pseudomonas aeruginosa andAcinetobacter baumannii.

In the following, general preparation process of the compound of thepresent application will be explained.

The compounds applied to investigation and evaluation of the presentinvention can be synthesized by using the side chain-forming compound(A-BH) and the carboxylic acid represented by the formula (6b) accordingto the following scheme 1:

in the above scheme, OBn represents benzyloxy,

-   including the method disclosed in U.S. Pat. No. 7,112,592, by    carrying out modification and improvement of the reaction    conditions, post-treatment and purification step in view of the    reactivity specific for the respective functional groups or the    stability specific for the respective compounds.

That is, an optically active carboxylic acid represented by the formula(6b) and the side chain-forming compound (A-BH) are treated by a methodselected from the mixed acid anhydride method, the active esterifyingmethod, the active amidating method or the dehydration condensing agentin the presence of a base to prepare a compound represented by theformula (Ia), the benzyl of the benzyloxy of the formula (Ia) issubjected to hydrogenolysis reaction under hydrogen atmosphere in thepresence of a catalyst selected from platinum oxide, palladium oxide,palladium black and palladium-carbon, and if necessary, in the presenceof di-tert-butoxydicarbonate, to prepare a compound represented by theformula (Ib), the hydroxyl group of the formula (Ib) is sulfated by asulfating agent selected from sulfur trioxide-pyridine complex, sulfurtrioxide-dimethylformamide complex and chlorosulfonic acid in thepresence of a base selected from pyridine, 2-picoline, 2,6-lutidine and2,4,6-collidine to prepare a compound represented by the formula (Ic),and if necessary, the protective group for the amino group (for example,tert-butoxycarbonyl group (Boc)) on the side chain is gently treatedwith an acid (for example, selected from hydrochloric acid, sulfuricacid, methanesulfonic acid, p-toluenesulfonic acid,trifluoromethanesulfonic acid, trifluoro-acetic acid or tetrafluoroboricacid, etc.) to deprotect it, and then, the compound represented by theformula (Id) is purified by octadecyl silica gel column chromatography,column chromatography using a synthetic resin such as DIAION HP21(available from Mitsubishi Chemical Corporation), SEPABEADS SP207(available from Mitsubishi Chemical Corporation) or preparative HPLC,etc., at a suitable pH, etc., whereby the objective compound can besynthesized.

The optically active carboxylic acid represented by the above formula(6b) can be synthesized by the following scheme 2:

in the above scheme, Cbz represents benzyloxycarbonyl, t-Bu represents atert-butyl, TFAA represents trifluoroacetic acid anhydride, TFA bondedto the compound represents trifluoroacetyl, Tf₂O representstrifluoromethanesulfonic acid anhydride, BnONH₂ representsbenzyloxyamine, DMAP represents 4-dimethylaminopyridine, TFA solelydescribed in the scheme represents trifluoroacetic acid, OBn representsbenzyloxy, and LiOH represents lithium hydroxide,

-   and the method shown in the Examples of the present invention.

That is, the benzyloxycarbonyl of the known compound represented by theformula (1) is removed by the hydrogenolysis reaction in the presence ofa catalyst such as palladium-carbon under hydrogen atmosphere to preparea compound represented by the formula (2); converting it by reactingwith trifluoroacetic acid anhydride in the presence of triethylamine toprepare a compound represented by the formula (3); reacting the hydroxylgroup at the 5-position thereof with trifluoromethanesulfonic acidanhydride in the presence of 2,6-lutidine, subsequently withbenzyloxyamine to prepare a compound represented by the formula (IV);removing the trifluoroacetyl by using sodium hydroxide to prepare acompound represented by the formula (4a), or subjecting to removal ofthe trifluoroacetyl by using hydrogen chloride-methanol and an esterexchange reaction simultaneously to prepare a compound represented bythe formula (4b); reacting them with diphosgene or phosgene in thepresence of triethylamine or 4-dimethylaminopyridine to prepare acompound represented by the formula (5a) or (5b); and cleaving the esterat the 2-position by an acid treatment using trifluoroacetic acid, etc.,or a base treatment using lithium hydroxide, etc., to prepare(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid represented by the formula (6b). Or else, commercially available(2S,5S)-5-hydroxypiperidine-2-carboxylic acid represented by the formula(7) or a hydrochloride thereof is derived to the compound represented bythe formula (10) or (4b) according to the similar method as mentionedabove without purification, and isolated as a hydrochloride thereof, andfurther the procedure is carried out to obtain(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid represented by the formula (6b).

Among the side chain-forming compound A-BH, the specific hydrazinederivative represented by Ra(Rb)N-BH can be synthesized by the followingscheme 3:

in the above scheme, Cbz represents benzyloxycarbonyl.

-   That is, it can be easily synthesized by subjecting to the reaction    of an ester and hydrazine.monohydrate, amidating an acid chloride    and N-benzyloxycarbonyl hydrazine in the presence of a suitable    base, or amidating a carboxylic acid and N-benzyloxycarbonyl    hydrazine by a dehydration condensing agent or by the mixed acid    anhydride method, and then, subjecting the benzyloxycarbonyl group    to hydrogenolysis in the presence of a catalyst such as    palladium-carbon.

Also, a specific alkoxyamine represented by RcOBH is synthesized by themethod shown in the following scheme 4:

That is, it can be easily synthesized by subjecting N-hydroxyphthalimideand a suitable alcohol derivative to coupling according to Mitsunobureaction, or reacting with an alkylating agent having a leaving groupsuch as alkyl halide and a methylsulfonyloxy group, then, deprotectingthe phthalimide by an organic base such as hydrazine.monohydrate ormethylamine

In the following, a process for preparing the compound represented bythe following formula (III):

in the above formula (III), Rc represents a C₁₋₆ alkyl or aheterocyclyl; B represents NH or NC₁₋₆ alkyl; M represents H, aninorganic cation or an organic cation; Rc may be modified by 0 to 4substituents Fn1, where the substituent Fn1 may be substitutedcontinuously; Fn1 represents C₁₋₆ alkyl, O═ or Rg-(CH₂)₀₋₃—, where Rgrepresents a heterocyclyl, phenyl, heteroaryl, acyl, RdO₂S—, Re(Rf)N—,Re(Rf)NCO—, ReO—, ReOCO— or a protective group, where Rd represents C₁₋₆alkyl or MO—; Re and Rf each independently represent H or C₁₋₆ alkyl;and between Rc-B, and between Re-Rf may be closed by the bonding to forma heterocyclyl having at least one nitrogen atom, to be provided in thepresent invention will be explained in more detail.

In the preparation process of the present invention, as the suitableprotective group represented by P¹ in a starting material represented bythe following formula (IV-a):

in the above formula (IV-a), P¹ represents a protective group which canbe removed by an acid, a base or a nucleophilic agent; and OBnrepresents benzyloxy, the protective group for an amino group capable ofdeprotecting by an acid, a base or a nucleophilic agent described inProtective Groups in Organic Synthesis (T. W. Greene et al., Wiley, NewYork (1999)) can be employed. More specifically, there may be mentionedtert-butoxycarbonyl, 2-trimethylsilylethoxycarbonyl,1,1-dimethylpropinyl-oxycarbonyl,1-methyl-1-(4-biphenylyl)ethoxycarbonyl, 1-methylcyclobutoxycarbonyl,1-adamantyloxycarbonyl, diphenylmethoxycarbonyl,9-fluorenylmethoxycarbonyl, 1,1-dimethyl-2-cyanoethoxycarbonyl, formyl,trichloroacetyl, trifluoroacetyl, benzene-sulphenyl,2-nitrobenzenesulphenyl, 2-trimethylsilylethanesulfonyl,2-nitrobenzene-sulfonyl, 4-nitrobenzenesulfonyl,2,4-dinitrobenzenesulfonyl, 2-naphthalenesulfonyl, 9-anthrathenesulfonyland benzenethiazole sulfonyl, preferably tert-butoxycarbonyl,2-trimethylsilylethoxycarbonyl, trifluoroacetyl,9-fluorenylmethoxycarbonyl, 2-nitrobenzenesulfonyl or4-nitrobenzenesulfonyl.

The step of obtaining a compound represented by the following formula(IV-b):

in the above formula (IV-b), P¹ represents a protective group which canbe removed by an acid, a base or a nucleophilic agent, Rc and B have thesame meanings as defined for the compound represented by the formula(III), and OBn represents benzyloxy, by coupling the compoundrepresented by the formula (IV-a) with the side chain-forming compound:RcOBH, can be carried out by the method where the compound representedby the formula (IV-a) is treated by using an active ester, an activeamide or the dehydration condensing agent in a suitable solvent.

Coupling using the dehydration condensing agent is carried out in manycases by adding an active ester group or an active amide group as acatalyst to form an active ester or an active amide in the reactionsystem, and the specific examples are mentioned and explained below.

The solvent to be used for the dehydration condensing agent may bementioned water, methanol, ethanol, isopropanol, ethyl acetate, toluene,tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform,dimethylformamide, dimethylacetamide, etc., preferably ethyl acetate,tetrahydrofuran, dichloromethane, acetonitrile, dimethylform-amide,dimethylacetamide, which can be used singly or in admixture.

When the active esterifying agent or the active amidating agent is used,the reaction is carried out in the presence of a base, if necessary. Thebase to be used in the reaction may be mentioned triethylamine,diisopropylethylamine, tributylamine, N-methylmorpholine and4-dimethylaminopyridine, preferably triethylamine, and used in the rangeof 1 to 3 equivalents depending on necessity based on the compoundrepresented by the formula (IV-a), preferably 1 to 1.5 equivalents.

As the dehydration condensing agent, there may be used carbodiimidealone such as N,N′-diisopropylcarbodiimide,N,N′-dicyclohexylcarbodiimide and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, or incombination with an active amide group or an active ester group such asimidazole, 1-hydroxybenzotriazole mono-hydrate, N-hydroxysuccinimide and2-hydroxypyridine-N-oxide, and further there may be mentioned an activeesterifying agent or an active amidating agent such ascarbonyldiimidazole, benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate, 2-chloro-1-methylpyridinium iodide and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloridein combination with 1-hydroxybenzotriazole monohydrate, or selected2-chloro-1-methylpyridinium iodide, and the agent is used in the rangeof 1.0 to 2.0 equivalents based on the compound represented by theformula (IV-a), more preferably 1.0 to 1.5 equivalents. The reactiontemperature is in the range of −40° C. to room temperature, preferablyin the range of −20° C. to room temperature. The reaction is carried outwith a time in the range of 30 minutes to 1 day, preferably in the rangeof 2 hours to 16 hours.

The compound represented by the formula (IV-b) can be isolated bydiluting the reaction mixture with a suitable solvent after completionof the reaction, washing successively with water, a diluted acid, anaqueous base solution (for example, diluted hydrochloric acid, potassiummonohydrogen sulfate, citric acid, or an aqueous sodium bicarbonatesolution, saturated saline solution), and evaporating the solvent toconcentrate the reaction mixture. The organic solvent to be used fordilution may be mentioned diethyl ether, ethyl acetate, butyl acetate,toluene, dichloromethane and chloroform, preferably ethyl acetate.

Subsequently, the step of deprotecting the compound represented by theabove formula (IV-b) to prepare a compound represented by the followingformula (IV-c):

in the above formula (IV-c), Rc and B have the same meanings as definedfor the compound represented by the formula (III), and OBn representsbenzyloxy, can be carried out as follows.

The solvent to be used for deprotecting under the acidic conditions maybe mentioned water, methanol, ethanol, isopropanol, ethyl acetate,tetrahydrofuran, dioxane, dichloromethane, chloroform,1,2-dichloroethane, 2,2,2-trifluoroethanol, etc., preferably water,methanol, ethanol, ethyl acetate, dioxane and dichloromethane, which canbe used singly or in admixture.

The acid to be used for deprotecting under the acidic conditions may bementioned hydrochloric acid, sulfuric acid, phosphoric acid, formicacid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, chloromethanesulfonic acid,tetrafluoroboric acid, etc., preferably hydrochloric acid, sulfuricacid, trifluoroacetic acid, methanesulfonic acid and tetrafluoroboricacid, more preferably hydrochloric acid or trifluoroacetic acid. Theacid is used in the range of 1 equivalent to a solvent amount based onthe compound represented by the formula (IV-b), preferably 5-fold amountto a solvent amount. The reaction temperature is in the range of −25 to50° C., preferably in the range of −10 to 30° C. The reaction is carriedout with a time in the range of 30 minutes to 16 hours, preferably inthe range of 30 minutes to 5 hours.

The solvent to be used for deprotecting under basic conditions or by thenucleophilic agent may be mentioned water, methanol, ethanol,isopropanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide,dimethylacetamide, 2,2,2-trifluoroethanol, etc., preferably water,methanol, tetrahydrofuran and dioxane, which can be used singly or inadmixture.

The base to be used for deprotecting under basic conditions may bementioned lithium hydroxide, sodium hydroxide, potassium hydroxide,cesium hydroxide, lithium carbonate, sodium carbonate, potassiumcarbonate, cesium carbonate, etc., preferably lithium hydroxide, sodiumhydroxide and potassium hydroxide, and is used in the range of 2 to 5equivalents based on the compound represented by the formula (IV-b),preferably in the range of 2 to 4 equivalents. The reaction temperatureis in the range of −25 to 50° C., preferably 0 to 10° C. The reaction iscarried out with a time in the range of 30 minutes to 16 hours,preferably in the range of 30 minutes to 5 hours.

The nucleophilic agent to be used for deprotecting by the nucleophilicagent may be mentioned a thiol such as ethanethiol, thioglycolic acidand thiophenol; and a fluoride such as hydrogen fluoride pyridine,sodium fluoride, potassium fluoride, cesium fluoride andtetrabutylammonium fluoride, preferably tetrabutylammonium fluoride, andis used in the range of 2 to 4 equivalents based on the compoundrepresented by the formula (IV-b), preferably 2 to 3 equivalents. Thereaction temperature is selected from the range of 0 to 100° C.,preferably 25 to 60° C. The reaction is carried out with a time in therange of 2 hours to 48 hours, preferably 8 hours to 24 hours.

The compound represented by the formula (IV-c) having the RcONHCO groupwith a weak acidic property is an amphoteric substance, so that there isan optimum pH range for obtaining the compound as a free base. Theoptimum pH is in the range of pH6 to 9, preferably in the range of pH6to 8.

The compound represented by the formula (IV-c) can be isolated bydiluting the reaction mixture with an organic solvent, adjusting theoptimum pH as mentioned above, and extracting with a solvent. Theorganic solvent to be used for diluting the basic reaction mixture maybe mentioned diethyl ether, ethyl acetate, butyl acetate, toluene,dichloromethane and chloroform, preferably ethyl acetate ordichloromethane. Subsequently, the step of silylating the compoundrepresented by the above formula (IV-c) in the reaction system, andcontinuously subjecting to intramolecular urea formation reaction toobtain a compound represented by the following formula (IIa):

in the above formula (IIa), Rc and B have the same meanings as definedfor the compound represented by the formula (III), and OBn representsbenzyloxy, can be carried out as follows.

The solvent to be used for the reaction may be mentioned ethyl acetate,tetrahydrofuran, dioxane, acetonitrile, dimethylformamide,dimethylacetamide, etc., preferably acetonitrile is selected.

The base to be used for the reaction may be mentioned triethylamine,diisopropylethylamine, tributylamine and N-methylmorpholine, preferablytriethylamine, and is used in the range of 3 to 6 equivalents based onthe compound represented by the formula (IV-c), preferably 3 to 4equivalents.

The silylating agent to be used for the reaction may be mentioned achlorotrialkylsilane such as chlorotrimethylsilane,chlorotriethylsilane, chlorotriisopropylsilane andchloro-tert-butyldimethylsilane; trimethylsilyltrifluoromethanesulfonate and tert-butyldimethylsilyltrifluoromethanesulfonate, preferably a chlorotrialkylsilane such aschlorotrimethylsilane, and is used in the range of 1 to 3 equivalentsbased on the compound represented by the formula (IV-c), preferably 1 to1.5 equivalents.

The urea-forming agent to be used for the reaction may be mentionedphosgene, diphosgene, triphosgene and carbonyldiimidazole, preferablyphosgene and diphosgene, and is used in the range of 0.5 to 2equivalents based on the compound represented by the formula (IV-c),preferably 0.5 to 1.0 equivalent. At that time, to complete the ureaformation, a catalytic amount of 4-dimethylaminopyridine is used in therange of 0.1 to 1 equivalent based on the compound represented by theformula (IV-c), preferably 0.1 to 0.2 equivalent.

The reaction temperature is in the range of −25 to 50° C., preferably−15 to 30° C. The reaction is carried out with a time in the range of 10minutes to 24 hours, preferably 1 hour to 16 hours.

The formed compound represented by the formula (V-2) can be isolated bythe conventional post-treatment such as evaporating the organic solventof the reaction mixture to concentrate the same, diluting with asolvent, washing with an acid and a base, drying, evaporating thesolvent to concentrate the same, and precipitation.

Subsequently, the step of preparing a compound represented by thefollowing formula (IIb):

in the above formula (IIb), Rc and B have the same meanings as definedfor the compound represented by the formula (III),

-   by cleaving the benzyl group of the benzyloxy group at the    6-position of the compound represented by the above formula (IIa)    using a hydrogenolysis catalyst under hydrogen atmosphere can be    carried out as follows.

The solvent to be used for the reaction may be mentioned water,methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran anddioxane, preferably methanol or tetrahydrofuran, which can be usedsingly or in admixture.

The hydrogenolysis catalyst may be mentioned platinum oxide, palladiumhydroxide, palladium black or palladium-carbon, preferablypalladium-carbon.

An amount of the catalyst is employed in the range of 5 to 100 wt %based on the compound represented by the formula (IIa), preferably 5 to30 wt %.

A supply source of the hydrogen to be used for the hydrogenolysis is ahydrogen gas, and a hydrogen pressure is selected in the range ofatmospheric pressure to 1 MPa, preferably atmospheric pressure to 0.5MPa. As the supply source of the hydrogen, ammonium formate, cyclohexeneor cyclohexadiene can be used as the other method. An amount of thehydrogen to be supplied is used at least stoichiometric amount.

The reaction temperature of the hydrogenolysis is in the range of 10 to50° C., preferably in the range of 15 to 30° C. The reaction is carriedout with a time in the range of 0.5 to 3 hours, preferably in the rangeof 0.5 to 2 hours.

When the amino group and the benzyloxycarbonyl group as the protectivegroup therefor are present in the side chain Rc of the compoundrepresented by the formula (IIa), they can be protected again by thetert-butoxycarbonyl group in the presence ofdi-tert-butoxycarbonyldicarbonate simultaneously with theabove-mentioned hydrogenolysis reaction.

An amount of the di-tert-butoxycarbonyldicarbonate to be added is 1 to 2equivalents based on the compound represented by the formula (IIa),preferably 1 to 1.2 equivalents. After completion of the reaction, thecompound represented by the formula (IIb) can be isolated by the usualoperations such as filtration of the catalyst, and evaporation of thesolvent to concentrate the mixture.

Subsequently, the step of leading to the compound represented by theabove formula (III) by sulfating the hydroxyl group at the 6-position ofthe compound represented by the above formula (IIb) in the presence of abase, and deprotecting the protective group at the side chain (RcO), ifnecessary, can be carried out as follows.

The solvent to be used for sulfation may be mentioned water, methanol,ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethane,pyridine, acetonitrile and dimethylformamide, preferablydichloromethane, pyridine and acetonitrile, which can be used singly orin admixture.

The base to be used for the reaction may be mentioned triethylamine,tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,2-picoline, 3-picoline, 2,6-lutidine, 2,4,6-collidine,4-dimethylaminopiperidine and N-methyl-imidazole, preferably pyridine,2-picoline and 2,6-lutidine, and is used in the range of 1.0 to asolvent amount based on the compound represented by the formula (IIb),preferably in the range of 3.0 to a solvent amount.

The material to be used as the sulfating agent may be mentionedchlorosulfonic acid, sulfur trioxide-pyridine complex, sulfurtrioxide-dimethylformamide complex, sulfur trioxide-trimethylaminecomplex and sulfur trioxide-triethylamine complex, preferably sulfurtrioxide-pyridine complex or sulfur trioxide-dimethylformamide complex,and is used in the range of 1 to 4 equivalents based on the compoundrepresented by the formula (IIb), preferably 2 to 3 equivalents. Thereaction temperature is in the range of 0 to 50° C., preferably 10 to30° C. The reaction is carried out with a time in the range of 12 to 48hours, preferably in the range of 12 to 24 hours.

After completion of the reaction, the compound represented by theformula (III) can be obtained as a sulfonic acid pyridinium salt byfiltration and evaporation of the solvent to concentrate the reactionmixture, and by making a treatment with an aqueous inorganic basesolution containing sodium such as an aqueous sodium bicarbonatesolution to give a sodium salt, by adding 1 to 3 mol equivalents oftetrabutylammonium hydrogen sulfate to the aqueous solution of thesodium salt, and extracting with an organic solvent such as ethylacetate to give a tetrabutylammonium salt, and the above-mentionedaqueous solution is adjusted to the optimum pH to give an intramolecularsalt, to provide to the next step or the product is purified to preparea compound represented by the formula (III) as a final form.

Here, the optimum pH means the pH range at which the compoundrepresented by the formula (III) can be present stably as anintramolecular salt. The range of pH4 to 7 is selected to isolate thecompound as an intramolecular salt, more preferably in the range of pH5to 6.

When the protective group (for example, a tert-butoxycarbonyl group) ispresent at the side chain (RcO) of the formula (III), it is furtherapplied to the deprotection step.

As the step of deprotecting the tert-butoxycarbonyl group in the sidechain (RcO), deprotection under acidic conditions is employed.

The solvent to be used for the reaction may be mentioned water,methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dioxane,dichloromethane, chloroform, 1,2-dichloroethane, 2,2,2-trifluoroethanol,etc., preferably dichloromethane, ethyl acetate or2,2,2-trifluoroethanol.

The acid to be used for deprotection under acidic conditions may bementioned hydrochloric acid, sulfuric acid, phosphoric acid, formicacid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, chloromethanesulfonic acid,tetrafluoroboric acid, etc., preferably hydrochloric acid, sulfuricacid, trifluoroacetic acid, methanesulfonic acid and tetrafluoroboricacid, more preferably hydrochloric acid, sulfuric acid andtrifluoroacetic acid. The acid is used in the range of 1 equivalent to asolvent amount based on the compound represented by the formula (III),preferably 3-fold amount to a solvent amount. The reaction temperatureis in the range of −25 to 50° C., preferably −10 to 30° C. The reactionis carried out with a time in the range of 30 minutes to 5 hours,preferably in the range of 30 minutes to 1 hour.

After completion of the deprotection, the solvent of the reactionmixture is evaporated to concentrate the mixture or a poor solvent isadded to precipitate the crude product and then the mixture is made toan aqueous solution with the optimum pH in the range of pH5 to 6, and issubjected to precipitation again, or purification by using octadecylsilica (ODS), a synthetic resin such as DIAION HP-20 and SEPABEADSSP207, and an ion-exchange resin such as DOWEX 50W-X8 (Na type), furtherreprecipitation or lyophilization to obtain a compound represented bythe formula (III) as a final form.

Moreover, the preparation process of the compound represented by theabove formula (III) and(2S,5R)-7-oxo-N-(2-aminoethoxy)-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamiderepresented by the formula (III-059):

will be explained in detail.

The step of preparing (2S,5R)-methyl5-(benzyloxyamino)piperidine-2-carboxylate represented by the aboveformula (4b) or a hydrochloride thereof can be carried out as follows.

Methyl esterification of the commercially available(2S,5S)-5-hydroxy-piperidine-2-carboxylic acid represented by theformula (7) or a hydrochloride thereof is carried out in methanol underheating in the presence of a suitable acid. The acid to be used may bementioned hydrogen chloride, sulfuric acid, perchloric acid,methane-sulfonic acid and p-toluenesulfonic acid, preferably hydrogenchloride. When hydrogen chloride is used, it is used in an amount of 3to 6 equivalents, preferably 4 to 5 equivalents based on an amino acidmolar number/weight ratio obtained from an acid/base consuming amount ofthe compound represented by the formula (7). The reaction is carried outunder reflux for 2 to 4 hours, preferably 3 hours. After completion ofthe reaction, the residue obtained by concentrating the reaction mixtureis made basic, and extracted with a suitable organic solvent to isolate(2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate represented by theformula (8). The base to be used may be mentioned sodium hydroxide,sodium carbonate and potassium carbonate, preferably potassiumcarbonate. The solvent to be used for extraction may be mentioneddiethyl ether, ethyl acetate, dichloromethane, chloroform, preferablyethyl acetate. The isolated compound represented by the formula (8) canbe applied to the next step without further purification.

Trifluoroacetylation of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylaterepresented by the formula (8) is carried out by the reaction withtrifluoroacetic anhydride in the presence of triethylamine Thetrifluoroacetic anhydride is used in an amount in the range of 0.9 to1.3 equivalents, preferably 1.0 equivalent based on the sum total of amolar number/weight ratio of the compound represented by the formula (8)obtained by the pre-labeled HPLC method and an amino acid molarnumber/weight ratio obtained from an acid consuming amount. Also,triethylamine is used in an amount double as much of that oftrifluoroacetic anhydride. The reaction solvent is selected fromdichloromethane, chloroform, dichloroethane, ethyl acetate andtetrahydrofuran, preferably ethyl acetate. The reaction is carried outat a temperature in the range of −70° C. to 0° C., preferably -40° C. to0° C., and a reaction time in the range of 60 to 120 minutes, preferably60 to 90 minutes. (2S,5S)-methyl5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate representedby the formula (9) can be isolated by adding water to the reactionmixture to hydrolyze the trifluoroacetoxy group at the 5-position alone,then washing with usual acid/base and concentrating the mixture underreduced pressure. The isolated compound represented by the formula (9)can be applied to the next step without further purification.

The step of benzyloxyamination of the hydroxyl group at the 5-positionof (2S,5S)-methyl5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate representedby the formula (9) can be carried out by reacting it withtrifluoromethanesulfonic anhydride in an amount of 1 to 1.1 equivalents,preferably 1 equivalent in the presence of 2,6-lutidine in an amount of1 to 1.2 equivalents, preferably 1.1 equivalents based on the HPLC titerof the compound represented by the formula (9) in the reaction system toprepare a trifluoromethanesulfonic acid ester, subsequently reacting theresulting compound with benzyloxyamine in an amount of 1 to 3equivalents, preferably 2 equivalents in the presence of 2,6-lutidine inan amount of 1 to 1.2 equivalents, preferably 1.1 equivalents. Thereaction solvent is selected from dichloromethane, chloroform,1,2-dichloromethane, tetrahydrofuran and acetonitrile, preferablyacetonitrile. The reaction is carried out at a temperature in the rangeof −50° C. to 50° C., preferably −35° C. to 0° C., and a reaction timein the range of 1 to 5 days, preferably 2 to 3 days. (2S,5R)-methyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylaterepresented by the formula (10) can be isolated and purified byconcentrating the reaction mixture under reduced pressure, diluting theresidue with a solvent such as ethyl acetate, etc., washing with usualacid/base, and concentrating the mixture under reduced pressure toprepare a crude compound represented by the formula (10), then,dissolving the crude product in ethyl acetate and adding a hydrogenchloride-ethyl acetate solution thereto to obtain a hydrochloride of thecompound represented by the formula (10).

Removal of the 2,2,2-trifluoroacetyl group of (2S,5R)-methyl5-(benzyloxy-amino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylaterepresented by the formula (10) can be carried out in methanol underheating in the presence of a suitable acid. The acid to be used issuitably hydrogen chloride, sulfuric acid, perchloric acid,methanesulfonic acid and p-toluenesulfonic acid, preferably hydrogenchloride. An amount of hydrogen chloride to be used is in the range of10 to 20 equivalents, preferably 13 to 18 equivalents based on theamount of the compound represented by the formula (10). The reactiontime is 1 to 4 days, preferably 1 to 3 days. When an acid other thanhydrogen chloride is used, the residue obtained by concentrating thereaction mixture under reduced pressure is made basic, a free base of(2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate represented by theformula (4b) is once extracted with a suitable organic solvent, andthen, an acid selected from oxalic acid and hydrogen chloride is addedthereto to isolate and purify the objective compound as a salt. Whenhydrogen chloride is used, the reaction mixture is concentrated andethyl acetate is added as a poor solvent to isolate and purify ahydrochloride of the compound represented by the formula (4b).

Here, the compound represented by the formula (4b) can be easilyisolated and purified as a hydrochloride by crystallization so that itis an intermediate industrially extremely advantageous.

The compound represented by the following formula (IV-a2), (IV-a3) or(IV-a4):

in the above formula (IV-a2), (IV-a3) or (IV-a4), TFA representstrifluoroacetyl, Boc represents tert-butoxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy,

-   can be prepared by the following scheme 5:

-   in the above scheme, the free TFA represents trifluoroacetic acid,    TFA bonded to the chemical formula represents trifluoroacetyl, t-Bu    represents tert-butyl, OBn represents benzyloxy, Boc₂O represents    di-tert-butoxydicarbonate, TeocO-Su represents    N-(2-trimethylsilylethoxycarbonyloxy)succinimide, Boc represents    tert-butoxycarbonyl, and Teoc represents    2-trimethylsilylethoxycarbonyl,-   from the compound represented by the formula (IV) or the formula    (4b) in the synthetic scheme 2 of the optically active carboxylic    acid (6b), and by the method shown in Examples.

That is, the compound represented by the formula (IV-a2) can be preparedby cleaving the tert-butoxy ester of the compound represented by theformula (IV) with a solvent amount of trifluoroacetic acid in a halogenseries solvent such as dichloromethane and chloroform.

Also, the compound represented by the formula (IV-al) can be obtained byremoving the trifluoroacetyl of the compound represented by the formula(IV) with a base selected from sodium hydroxide and potassium hydroxidein hydrated dioxane, cleaving the tert-butoxy ester by an acid selectedfrom hydrochloric acid, sulfuric acid, trifluoroacetic acid ormethanesulfonic acid to prepare a salt of the compound represented bythe formula (IV-a1), which can be used in the next step after isolationor without isolation. In addition, the methyl ester of the hydrochlorideof the compound represented by the formula (4b) is cleaved under thesimilar basic conditions to prepare a solution of the compoundrepresented by the formula (IV-a1) and the compound can be used in thenext step without isolation.

The compounds represented by the formulae (IV-a3) and (IV-a4) can beprepared by dissolving the compound represented by the formula (IV-a1)in aqueous dioxane or aqueous tetrahydrofuran, and reacting with atert-butoxycarbonylating agent selected from Boc₂O(di-tert-butoxydicarbonate), Boc-ON(2-(tert-butoxycarbonyloxy-imino)-2-phenylacetonitrile) and Boc-OSu(N-(tert-butoxycarbonyloxy)succinimide), or withN-(2-trimethylsilylethoxycarbonyloxy)succinimide in the presence of abase selected from sodium hydroxide, sodium carbonate, potassiumcarbonate and triethylamine.

-   (2S,5R)-5-(benzyloxyamino)piperidin-2-carboxylic acid,-   (2S,5R)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidin-2-carboxylic    acid,-   (2S,5R)-5-(benzyloxyamino)-1-(tert-butoxycarbonyl)piperidin-2-carboxylic    acid, and-   (2S,5R)-5-(benzyloxyamino)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidin-2-carboxylic    acid,    which are the formulae (IV-a1), (IV-a2), (IV-a3) and (IV-a4),    respectively, in the above scheme 5 are each novel compound, and    they have usefulness not only in the field of the present invention    but also general starting materials.

Among the above formulae (IV-a2), (IV-a3) and (IV-a4), the step ofobtaining the compound represented by the following formula(IV-b2-Boc-059), (IV-b3-Cbz-059), (IV-b4-Boc-059):

in the above formula (IV-b2-Boc-059), (IV-b3-Cbz-059), (IV-b4-Boc-059),TFA represents trifluoroacetyl, Boc represents tert-butoxycarbonyl, Cbzrepresents benzyloxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy, bysubjecting to coupling the compounds represented by the formulae (IV-a2)and (IV-a4) by the method of using tert-butyl 2-(aminooxy)ethylcarbamateand an active ester, an active amide or a dehydration condensing agent,and by subjecting to coupling the compound represented by the formula(IV-a3) by the method of using benzyl 2-(aminooxy)ethylcarbamate and anactive ester, an active amide or a dehydration condensing agent can becarried out as follows.

An amount of the tert-butyl 2-(aminooxy)ethylcarbamate or benzyl2-(aminooxy)ethylcarbamate to be used is 1 to 2 equivalents based on thecompound represented by the formula (IV-a2), (IV-a3) or (IV-a4),preferably 1.0 to 1.5 equivalents.

Coupling using the dehydration condensing agent is carried out in manycases by adding an active ester group or an active amide group as acatalyst to form an active ester or an active amide in the reactionsystem, and the specific examples are mentioned and explained below.

The solvent to be used when the dehydration condensing agent is used maybe mentioned ethyl acetate, toluene, tetrahydrofuran, dioxane,acetonitrile, dichloro-methane, chloroform, dimethylformamide,dimethylacetamide, etc., preferably ethyl acetate, tetrahydrofuran,dichloromethane, acetonitrile, dimethylformamide and dimethylacetamide.

When an active esterifying agent or an active amidating agent is used,the reaction is carried out in the presence of a base, if necessary. Thebase to be used for the reaction may be mentioned triethylamine,diisopropylethylamine, tributylamine, N-methylmorpholine and4-dimethylaminopyridine, preferably triethylamine, and is used in therange of 1 to 3 equivalents based on the compound represented by theformula (IV-b2-Boc-059), (IV-b3-Cbz-059) or (IV-b4-Boc-059) depending onnecessity, preferably 1 to 1.5 equivalents.

The dehydration condensing agent may be used carbodiimide alone such asN,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, or acombination with an active ester group such as1-hydroxybenzotriazolemonohydrate, N-hydroxysuccinimide and2-hydroxypyridine-N-oxide, and further an active amidating agent or anactive esterifying agent such as carbonyldiimidazole,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate,2-chloro-1-methylpyridinium iodide and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,preferably 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloridein combination with 1-hydroxybenzotriazole -monohydrate, or selected2-chloro-1-methylpyridinium iodide, and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is used inthe range of 1 to 2 mol equivalents and 1-hydroxybenzotriazolemonohydrate in the range of 1 to 2 equivalents based on the compoundrepresented by the formula (IV-a2), (IV-a3) or (IV-a4), preferably 1 to1.3 equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride and 0.1 to 0.3 equivalent of1-hydroxybenzotriazolemonohydrate. The reaction temperature is in therange of −40° C. to room temperature, preferably in the range of −20° C.to room temperature. The reaction is carried out with a time in therange of 30 minutes to 1 day, preferably 2 hours to 16 hours.

The compound of the formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or(IV-b4-Boc-059) which is a coupling product can be isolated aftercompletion of the reaction, by diluting the reaction mixture with asuitable solvent, washing successively with water, a diluted acid, anaqueous base solution (for example, diluted hydrochloric acid, potassiummonohydrogen sulfate, citric acid, or an aqueous sodium bicarbonatesolution), and evaporating the solvent to concentrate the reactionmixture. The organic solvent to be used for dilution may be mentioneddiethyl ether, ethyl acetate, butyl acetate, toluene, dichloromethaneand chloroform, preferably ethyl acetate.

Then, the step of removing the trifluoroacetyl group of the compoundrepresented by the above formula (IV-b2-Boc-059) by a base treatment toprepare a compound represented by the following formula (IV-c-Boc-059):

in the above formula (IV-c-Boc-059) or (IV-c-Cbz-059), Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, can be carried out as follows.

The solvent to be used for removal of the trifluoroacetyl group may bementioned water, methanol, ethanol, isopropanol, tetrahydrofuran,dioxane, dichloromethane, chloroform, 1,2-dichloroethane, etc.,preferably water, methanol, tetrahydrofuran and dioxane, which may beused singly or in admixture, more preferably aqueous dioxane ortetrahydrofuran.

The base to be used may be mentioned lithium hydroxide, sodiumhydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate,sodium carbonate, potassium carbonate, cesium carbonate, etc.,preferably lithium hydroxide, sodium hydroxide and potassium hydroxide,more preferably sodium hydroxide, and is used in the range of 2 to 4equivalents based on the compound represented by the formula (IV-b2),preferably 2 to 3 equivalents.

The reaction temperature is in the range of −20 to 30° C., preferably inthe range of 0 to 10° C. The reaction is carried out with a time in therange of 1 to 16 hours, preferably in the range of 1 to 3 hours.

The compound represented by the formula (IV-c-Boc-059) having theRcONHCO group which shows a weak acidic property is an amphotericsubstance, so that there is an optimum pH range for obtaining thecompound as a free base. The optimum pH is in the range of pH6 to 9,preferably in the range of pH6 to 8.

The compound represented by the formula (IV-c-Boc-059) can be isolatedby diluting the reaction mixture with an organic solvent, adjusting themixture to the optimum pH, and extracting the mixture with a solvent.The organic solvent to be used for diluting the basic reaction mixturemay be mentioned diethyl ether, ethyl acetate, butyl acetate, toluene,dichloromethane and chloroform, preferably ethyl acetate ordichloromethane.

Also, the step of removing the tert-butoxycarbonyl group of the compoundrepresented by the above formula (IV-b3-Cbz-059) by an acid treatment toprepare a compound represented by the above formula (IV-c-Cbz-059) canbe carried out as follows.

The solvent to be used for removal of the tert-butoxycarbonyl group maybe mentioned water, methanol, ethanol, isopropanol, ethyl acetate,dioxane, dichloro-methane, chloroform, 1,2-dichloroethane and2,2,2-trifluoroethanol, preferably methanol, ethanol, ethyl acetate,dioxane and dichloromethane, which may be used singly or in admixture.

The acid to be used for the reaction may be mentioned hydrochloric acid,sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid,methanesulfonic acid, trifluoromethanesulfonic acid,chloromethanesulfonic acid and tetrafluoroboric acid, preferablyhydrochloric acid, sulfuric acid, methanesulfonic acid andtrifluoroacetic acid, more preferably hydrochloric acid ortrifluoroacetic acid. The acid is used in the range of 1 equivalent to asolvent amount based on the compound represented by the formula(IV-b3-Cbz-059), preferably 5-fold amount to a solvent amount.

The reaction temperature is in the range of −25 to 50° C., preferably inthe range of −10 to 30° C. The reaction is carried out with a time inthe range of 1 to 6 hours, preferably in the range of 1 to 3 hours.

The compound represented by the formula (IV-c-Cbz-059) having theRcONHCO group which shows a weak acidic property is an amphotericsubstance, so that there is an optimum pH range for obtaining thecompound as a free base. The optimum pH is in the range of pH6 to 9,preferably in the range of pH6 to 8.

The compound represented by the formula (IV-c-Cbz-059) can be isolatedby diluting the reaction mixture with an organic solvent, adjusting themixture to the optimum pH, and extracting the mixture with a solvent.The organic solvent to be used for diluting the basic reaction mixturemay be mentioned diethyl ether, ethyl acetate, butyl acetate, toluene,dichloromethane and chloroform, preferably ethyl acetate ordichloromethane.

The step of removing the 2-trimethylsilylethoxycarbonyl of the compoundrepresented by the above formula (IV-b4-Boc-059) by a fluoride toprepare a compound represented by the above formula (IV-c-Boc-059) canbe carried out as follows.

The solvent to be used for removal of the 2-trimethylsilylethoxycarbonylmay be mentioned water, methanol, ethanol, isopropanol, ethyl acetate,dioxane, tetrahydrofuran, acetonitrile, dimethylformamide anddimethylacetamide, preferably dioxane, tetrahydrofuran and acetonitrile.

The fluoride to be used for the reaction may be mentioned sodiumfluoride, potassium fluoride, cesium fluoride, hydrofluoric acid,hydrogen fluoride-pyridine, tetrabutylammonium fluoride, preferablytetrabutylammonium fluoride, and is used 2 to 6 equivalents based on thecompound represented by the formula (IV-b4-Boc-059), preferably 2 to 3equivalents.

The reaction temperature is in the range of 0 to 100° C., preferably inthe range of 25 to 60° C. The reaction is carried out with a time in therange of 1 to 48 hours, preferably in the range of 12 to 24 hours.

The compound represented by the formula (IV-c-Boc-059) can be isolatedby diluting the reaction mixture with an organic solvent, adjusting themixture to the optimum pH, and extracting the mixture with a solvent inthe same manner as in the formula (IV-b2-Boc-059). The organic solventto be used for diluting the basic reaction mixture may be mentioneddiethyl ether, ethyl acetate, butyl acetate, toluene, dichloromethaneand chloroform, preferably ethyl acetate.

Next, the step of preparing a compound represented by the followingformula (IIa-Boc-059) or (IIa-Cbz-059):

in the above formula (IIa-Boc-059) or (IIa-Cbz-059), Boc representstert-butoxy-carbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, by silylating the compound represented by theabove formula (IV-c-Boc-059) or (IV-c-Cbz-059) in the reaction system,continuously subjecting to intramolecular urea formation reaction can becarried out as follows.

The solvent to be used for the reaction may be mentioned ethyl acetate,tetrahydrofuran, dioxane, acetonitrile, dimethylformamide,dimethylacetamide, dichloromethane, chloroform, 1,2-dichloroethane,etc., preferably acetonitrile.

The organic base to be used for the reaction may be mentionedtriethylamine, diisopropylethylamine, tributylamine, N-methylmorpholine,etc., preferably triethylamine, and is used in the range of 3 to 6equivalents based on the compound represented by the formula(IV-c-Boc-059) or the formula (IV-c-Cbz-059), preferably 3 to 4equivalents.

The silylating agent to be used for the reaction may be mentioned achloro-trialkylsilane such as chlorotrimethylsilane,chlorotriethylsilane, chlorotriisopropyl-silane andchloro-tert-butyldimethylsilane; trimethylsilyltrifluoromethanesulfonate and tert-butyldimethylsilyltrifluoromethanesulfonate, preferably chlorotrimethylsilane, and is usedin the range of 1 to 3 equivalents based on the compound represented bythe formula (IV-c-Boc-059) or the formula (IV-c-Cbz-059), preferably 1to 2 equivalents.

The urea-forming agent to be used for the reaction may be mentionedphosgene, diphosgene, triphosgene and carbonyldiimidazole, preferablyphosgene and diphosgene, and is used in the range of 0.5 to 2equivalents based on the compound represented by the formula(IV-c-Boc-059) or the formula (IV-c-Cbz-059), preferably 0.5 to 1.0equivalent. At that time, to complete the urea formation, a catalyticamount of 4-dimethylaminopyridine is used in the range of 0.1 to 1equivalent based on the compound represented by the formula (IV-c),preferably 0.1 to 0.2 equivalent. The reaction temperature is in therange of −25 to 50° C., preferably −15 to 30° C. The reaction is carriedout with a time in the range of 10 minutes to 24 hours, preferably inthe range of 10 minutes to 16 hours.

The formed compound represented by the formula (IIa-Boc-059) or(IIa-Cbz-059) can be isolated by the conventional post-treatment such asevaporating the organic solvent of the reaction mixture to concentratethe same, diluting with a solvent, washing with an acid and a base,drying, and evaporating the solvent to concentrate the same.

Next, the step of preparing a compound represented by the followingformula (Hb-Boc-059):

in the above formula (IIb-Boc-059), Boc represents tert-butoxycarbonyl,

-   by cleaving the benzyl of the benzyloxy at the 6-position of the    compound represented by the formula (IIa-Boc-059) using a    hydrogenolysis catalyst under hydrogen atmosphere, or-   removing the benzyl of the benzyloxy at the 6-position of the    compound represented by the formula (IIa-Cbz-059) using a    hydrogenolysis catalyst under hydrogen atmosphere, and    simultaneously subjecting to tert-butoxycarbonylation can be carried    out as follows.

The solvent to be used for the reaction may be mentioned water,methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran anddioxane, preferably methanol or tetrahydrofuran, which may be usedsingly or in admixture.

The hydrogenolysis catalyst may be mentioned platinum oxide, palladiumhydroxide, palladium black or palladium-carbon, preferablypalladium-carbon.

An amount of the catalyst is employed in the range of 5 to 50 wt % inthe dry weight based on the compound represented by the formula (V-2),preferably 5 to 20 wt %.

A supply source of the hydrogen to be used for the hydrogenolysis is ahydrogen gas, and a hydrogen pressure is selected in the range ofatmospheric pressure to 1 MPa, more preferably atmospheric pressure to0.5 MPa. As the supply source of the hydrogen, ammonium formate,cyclohexene or cyclohexadiene can be used as another method. An amountof the hydrogen to be supplied is used at least stoichiometric amount.

The reaction temperature of the hydrogenolysis is in the range of 10 to50° C., preferably in the range of 15 to 30° C. The reaction is carriedout with a time in the range of 0.5 to 3 hours, preferably in the rangeof 0.5 to 2 hours. As in the compound represented by the formula(IIa-Cbz-059), when the compound has benzyloxycarbonyl separating fromthe benzyloxy at the 6-position, it can be protected again by thetert-butoxycarbonyl in the presence of di-tert-butoxycarbonyldicarbonatesimultaneously with the above-mentioned hydrogenolysis reaction.

An amount of the di-tert-butoxycarbonyldicarbonate to be added is 1 to 2equivalents based on the compound represented by the formula(IIa-Cbz-059), preferably 1 to 1.2 equivalents. After completion of thereaction, the compound represented by the formula (IIb-Boc-059) formedin the reaction system can be isolated by the usual operations such asfiltration of the catalyst, and evaporation of the solvent toconcentrate the mixture.

Next, the step of preparing a compound represented by the followingformula (III-Boc-059):

in the above formula (III-Boc-059), Boc represents tert-butoxycarbonyl,and M represents H, pyridinium, sodium or tetrabutylammonium,

-   by sulfating the hydroxyl group at the 6-position of the compound    represented by the formula (IIb-Boc-059) in the presence of an    organic base can be carried out as follows.

The solvent to be used for sulfation may be mentioned water, methanol,ethanol, isopropanol, dichloromethane, chloroform, 1,2-dichloroethane,pyridine, acetonitrile, dimethylformamide, etc., preferablydichloromethane, pyridine or acetonitrile.

The organic base to be used for the reaction may be mentionedtriethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine,pyridine, 2-picoline, 3-picoline, 2,6-lutidine, 2,4,6-collidine,4-dimethylaminopiperidine and N-methylimidazole, preferably pyridine,2-picoline and 2,6-lutidine, and is used in the range of 1.0 to asolvent amount based on the compound represented by the formula(IIb-Boc-059), preferably in the range of 3.0 to a solvent amount.

The material to be used as a sulfating reagent may be mentionedchlorosulfonic acid, sulfur trioxide-pyridine complex, sulfurtrioxide-dimethylformamide complex, sulfur trioxide-trimethylaminecomplex and sulfur trioxide-triethylamine complex preferably sulfurtrioxide-pyridine complex, and is used in the range of 1 to 4equivalents based on the compound represented by the formula(IIb-Boc-059), preferably 1 to 3 equivalents.

The reaction temperature is in the range of 0 to 50° C., preferably 10to 30° C. The reaction is carried out with a time in the range of 12 to48 hours, preferably in the range of 12 to 24 hours.

After completion of the reaction, the compound represented by theformula (III-Boc-059) can be obtained as a sulfonic acid pyridinium saltby filtration and evaporation of the solvent to concentrate the reactionmixture, and by treating it with an aqueous inorganic base solutioncontaining sodium such as an aqueous sodium bicarbonate solution to givea sodium salt, removing an excessive organic base by washing with asolvent and by adding 1 to 3 mol equivalents, preferably 1 to 2equivalents of tetrabutylammonium hydrogen sulfate, and extracting withan organic solvent such as ethyl acetate to give a tetrabutylammoniumsalt, which can be applied to the next step without purification.

Next, the step of preparing the above-mentioned (III-059) bydeprotecting the tert-butoxycarbonyl of the compound represented by theformula (III-Boc-059) with an acid selected from hydrochloric acid,sulfuric acid, methanesulfonic acid, trifluoroacetic acid andtetrafluoroboric acid can be carried out as follows.

The solvent to be used for the reaction may be mentioned water,methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dioxane,dichloromethane, chloroform, 1,2-dichloroethane, 2,2,2-trifluoroethanol,etc., preferably dichloromethane or 2,2,2-trifluoroethanol.

The acid to be used for deprotection under acidic conditions may bementioned hydrochloric acid, sulfuric acid, phosphoric acid, formicacid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, chloromethanesulfonic acid,tetrafluoroboric acid, etc., preferably hydrochloric acid, sulfuricacid, trifluoroacetic acid, methanesulfonic acid and tetrafluoroboricacid. The acid is used in the range of 1 equivalent to a solvent amountbased on the compound represented by the formula (III-Boc-059),preferably 5-fold amount to a solvent amount. The reaction is carriedout in the range of −25 to 50° C., preferably −10 to 30° C. The reactionis carried out with a time in the range of 30 minutes to 5 hours,preferably in the range of 30 minutes to 1 hour.

After completion of the deprotection, the solvent of the reactionmixture is evaporated to concentrate the mixture, the obtained residueis made an aqueous solution with an optimum pH, and subjected topurification with octadecyl silica (ODS), a synthetic resin such asHP-20 and SP207, or an ion exchange resin such as DOWEX 50W-X8 (Natype), evaporation of the solvent to concentrate the mixture andreprecipitation or lyophilization to give the compound represented bythe formula (III-059).

Here, the optimum pH means the pH range in which the compoundrepresented by the formula (III-059) is capable of existing stably as anintramolecular salt. The range of pH 4 to 7 is selected to isolate thecompound as an intramolecular salt, more preferably in the range of pH 5to 6.

EXAMPLES

Hereinafter, the present invention will be illustrated in more detail byexamples, but the present invention is not intended to be limited byexamples, with various modifications being possible.

Reference Example 1 (2S,5S)-1-Benzyl 2-tert-butyl5-hydroxypiperidine-1,2-dicarboxylate (1) Step 1: (S)-1-Benzyl2-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate

(S)-1-(Benzyloxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (100 g) wasdissolved in dehydrated methylene chloride (2 L), and under ice cooling,concentrated sulfuric acid (10 mL) and isobutene (213 g) were added,followed by stirring overnight at +20° C. or less. The reaction mixturewas added to cold aqueous sodium carbonate solution while payingattention to effervescence, followed by liquid separation of the organicphase, washing with saturated brine and drying over anhydrous magnesiumsulfate, then the solvent was concentrated under reduced pressure. Theresidue was subjected to silica gel column chromatography (hexane/ethylacetate=7/3), and crystallized with hexane/ethyl acetate to afford 80 gof the title compound as a colorless crystalline powder (yield 67%).Enantiomeric excess 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, UV 210nm, hexane/ethanol=2/1, flow rate 1 mL/min., retention time 4.2 min.).

-   [α]²⁰ _(D)−43.3° (c 0.52 in CHCl₃), according to Non-Patent Document    [Journal of Medicinal Chemistry 1991, 34(3), 956-968. Dolence, E K.;    Lin, C E.; Miller, M J.; Payne, S M. “Synthesis and siderophore    activity of albomycin-like peptides derived from    N5-acetyl-N5-hydroxy-L-ornithine”] −41.8° (c 6.71, CHCl₃); ¹H NMR    (400 MHz, CDCl₃) δ 1.39 (s, 9H), 2.04 (m, 1H), 2.32 (m, 1H), 2.51    (ddd, J=17.6, 9.5, 3.2 Hz, 1H), 2.62 (ddd, J=17.6, 10.5, 9.5 Hz,    1H), 4.55 (dd, J=9.5, 2.7 Hz, 1H), 5.25 (d, J=12.2 Hz, 1H), 5.30 (d,    J=12.2 Hz, 1H), 7.26-7.41 (m, 5H); MS m/z 320 (M+H).

Step 2: (5)-tert-Butyl2-(benzyloxycarbonylamino)-5-oxo-6-dimethylsulfoxonium hexanoate

To a solution of trimethylsulfoxonium iodide (70.2 g) in dehydratedN,N-dimethylformamide (585 mL), under an argon atmosphere, was addedpotassium tert-butoxide (36.8 g, 279 mmol), followed by stirring at roomtemperature for 1 hour. Then, at 5° C. or less, (S)-1-benzyl2-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate (87.0 g) was addedwithin 20 minutes (washed with dehydrated N,N-dimethylformamide (87mL)), followed by allowing to react at the same temperature for 1 hour.The reaction mixture was added to ice-cold water (2.6 L), saturated withsodium chloride, extracted with ethyl acetate (2.6 L×once, 1.3 L×twice,650 mL×4 times),and the solvent of the organic layer was distilled offunder reduced pressure. The resulting residue was subjected to silicagel column chromatography (heptane/ethyl acetate=1/2→ethylacetate/methanol=19/1→9/1) to afford 112.3 g of the title compound as apale yellow oil (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 1.95 (m, 1H), 2.09 (m, 1H),2.23-2.32 (m, 2H), 3.32 (s, 3H), 3.33 (s, 3H), 4.22 (m, 1H), 4.37 (s,1H), 5.07 (d, J=12.0 Hz, 1H), 5.13 (d, J=12.0 Hz, 1H), 5.75 (br d, J=8.0Hz, 1H), 7.30-7.36 (m, 5H); MS m/z 412 (M+H).

Step 3: (S)-1-Benzyl 2-tert-butyl 5-oxopiperidine-1,2-dicarboxylate

(S)-tert-Butyl 2-(benzyloxycarbonylamino)-5-oxo-6-dimethyl sulfoxoniumhexanoate (24.8 g) was dissolved in 1,2-dichloroethane (774 mL), and,after deaeration, dilx-chlorobis-[(η-cycloocta-1,5-diene)]diridium (I)(388.5 mg) was added under an argon atmosphere, followed by raising thetemperature and allowing to react at +70° C. for 2 hours. The solvent ofthe reaction mixture was distilled off under reduced pressure, and theresulting residue was subjected to silica gel column chromatography(hexane/ethyl acetate=2/1) to afford 14.55 g of the title compound as ared oil (yield 76%).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (s, 4.5H), 1.47 (s, 4.5H), 2.12-2.48 (m,4H), 3.93 (d, J=19.0 Hz, 0.5H), 4.00 (d, J=18.8 Hz, 0.5H), 4.37 (d,J=18.8 Hz, 0.5H), 4.46 (d, J=19.0 Hz, 0.5H), 4.62 (dd, J=7.3, 6.6 Hz,0.5H), 4.77 (dd, J=6.6, 5.9 Hz, 0.5H), 5.10-5.23 (m, 2H), 7.34-7.35 (m,5H); MS m/z 334 (M+H).

Step 4: (2S,5S)-1-Benzyl 2-tert-butyl5-hydroxypiperidine-1,2-dicarboxylate (1)

A solution of (S)-1-benzyl 2-tert butyl5-oxopiperidine-1,2-dicarboxylate (14.55 g) in ethanol (437 mL) wasice-cooled, and sodium borohydride (1.65 g) was added, followed byallowing to react under ice cooling for 20 minutes. Saturated aqueousammonium chloride solution was added dropwise to the reaction mixtureuntil effervescence was quenched, and the generated salt was dissolvedwith the addition of water. The organic solvent of the mixture wasdistilled off under reduced pressure, and the aqueous layer of theresidue was extracted with ethyl acetate. The organic layer was washedwith saturated brine, followed by drying over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresulting residue was subjected to silica gel column chromatography(hexane/ethyl acetate=3/1→2/1) to afford 13.35 g of the title compoundas a colorless oil (yield 91%). Enantiomeric excess 98.8% ee (CHIRALPAKAD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=4/1, flow rate 1 mL/min.,retention time 9.1 min.).

[α]²⁰ _(D)−29.7° (c 1.3, CHCl₃), according to Non-Patent Document[Tetrahedron Asymmetry 2006, 17(17), 2479-2486. Jung, J C.; Avery, M A.“Diastereoselective synthesis of (2S,5S)-and(2S,5R)—N-benzyloxycarbonyl-5-hydroxypipecolic acids fromtrans-4-hydroxy-L-proline”] −27.9° (c 2.0, CHCl₃); ¹H NMR (400 MHz,CDCl₃) δ 1.42 (s, 4.5H), 1.46 (s, 4.5H), 1.66-1.75 (m, 2H), 1.96-2.00(m, 2H), 2.24-2.30 (m, 1H), 2.74-2.80 (m, 0.5H), 2.84-2.90 (m, 0.5H),3.64 (br s, 1H), 4.15-4.20 (m, 0.5H), 4.23-4.27 (m, 0.5H), 4.65 (d,J=5.4 Hz, 0.5H), 4.78 (d, J=4.6 Hz, 0.5H), 5.07 (d, J=12.5 Hz, 1H), 5.21(d, J=12.5 Hz, 1H), 7.26-7.37 (m, 5H); MS m/z 334 (M+H).

Sequential synthesis of (2S,5S)-1-Benzyl 2-tert-butyl5-hydroxypiperidine-1,2-dicarboxylate (1)

(S)-tert-Butyl 2-(benzyloxycarbonylamino)-5-oxo-6-dimethyl sulfoxoniumhexanoate (112.3 g, 272 mmol) was dissolved in 1,2-dichloroethane (3.4L), and, after deaeration,di-μ-chlorobis-[(η-cycloocta-1,5-diene)]diiridium (I) (1.83 g) was addedunder an argon atmosphere, followed by raising the temperature to +70°C. within 1.75 hours and allowing to react for 1 hour. After cooling toroom temperature, the solvent of the reaction mixture was distilled offunder reduced pressure, and the resulting residue was dissolved inethanol (1.1 L). The mixture was ice-cooled, and sodium borohydride(5.14 g) was added within 10 minutes, followed by allowing to reactunder ice cooling for 20 minutes. Saturated aqueous ammonium chloridesolution (265 mL) was added dropwise to the reaction mixture untileffervescence was quenched, and the generated salt was dissolved withthe addition of water (250 mL). The organic solvent of the mixture wasdistilled off under reduced pressure, and the aqueous layer of theresidue was extracted with ethyl acetate (0.9 L×3 times). The solventwas distilled off under reduced pressure, and the resulting residue wassubjected to silica gel column chromatography (heptane/ethylacetate=3/1→2/1) to afford 66.82 g of the title compound as a colorlessoil (yield 73%). Instrumental data were consistent with those of Step 4of Reference Example 1.

Reference Example 2 Tetrahydro-2H-pyran-4-carbohydrazide

A solution of methyl tetrahydro-2H-pyran-4-carboxylate (1.44 g, 10.0mmol) in methanol (50 mL) was stirred at 50° C. To the reaction mixture,hydrazinemonohydrate (0.675 g) was added, followed by stirring at thesame temperature for 2 hours, after completion of the reaction, thereaction mixture was concentrated and diluted with methylene chloride,the solution was then washed with saturated sodium bicarbonate aqueoussolution and saturated brine, and the organic layer was dried overmagnesium sulfate and the solvent was distilled off under reducedpressure to afford 952 mg of the title compound (yield 66.1%).

¹H NMR (400 MHz, CD₃OD) δ 1.59-1.83 (m, 4H), 2.37-2.60 (m, 1H),3.38-3.47 (m, 2H), 3.87-3.96 (m, 2H); MS m/z 145 [M+H]⁺.

Reference Example 3 Benzyl 2-(furan-2-carbonyl)hydrazinecarboxylate

Benzyl hydrazinecarboxylate (1.66 g, 10.0 mmol) was dissolved intetrahydrofuran (20 mL) and water (20 mL) and added sodium hydrogencarbonate (1.68 g) thereto. Under ice cooling, furan-2-carbonyl chloride(1.30 g, 10 mmol) was gradually added, followed by stirring for 1 hour.After completion of the reaction, to the reaction solution was added 300ml of ethyl acetate, followed by washing with saturated ammoniumchloride solution and saturated brine. The organic layer was dried overmagnesium sulfate, the solvent was distilled off under reduced pressure,and 5 ml of ethyl acetate was dissolved in the resulting residue,followed by gradually adding hexane (100 ml) to afford 2.30 g of thetitle compound as a solid (yield 88.4%). ¹H NMR (400 MHz, CDCl₃) δ 5.18(s, 2H), 6.51 (m, 1H), 6.91(br s, 1H), 7.17 (m, 1H), 7.33 (m, 5H), 7.47(m, 1H), 8.17 (br s,1H); MS m/z 261 [M+H]⁺.

Reference Example 4 (R)-tert-Butyl 2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate

A solution of (R)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylicacid (1.146 g, 5.00 mmol) in dehydrated methylene chloride (25 mL) wascooled to 0° C. under an argon atmosphere and gradually added dropwiseisobutyl chloroformate (0.682 g) so that the temperature does not exceed0° C. Then, triethylamine (0.505 g) was gradually added so that thetemperature does not exceed 0° C., followed by stirring 30 minutes,thereby a mixed acid anhydride was prepared in the reaction system. Tothis reaction mixture was gradually added benzyl hydrazinecarboxylate(0.830 g), after the addition, followed by raising the temperature toroom temperature and stirring for 1 hour. This reaction mixture waswashed with 0.5M hydrochloric acid and saturated brine, the organiclayer was dried over magnesium sulfate and then distilled off underreduced pressure. The resulting residue was subjected to silica gelcolumn chromatography (hexane/ethyl acetate=4/1→0/1 ethylacetate/methanol=30/1) to afford 1.53 g of the title compound (yield80.1%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 2.20 (m, 2H), 2.45 (m, 1H), 2.63(m, 1H), 4.59 (br s, 1H), 5.16 (m, 2H), 6.84 (br s, 1H), 7.33 (m, 5H),8.17 (br s, 1H); MS m/z 378 [M+H]⁺.

Reference Example 5 (S)-tert-Butyl2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate

(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.076 g, 5.00mmol) was stirred under an argon atmosphere at room temperature withdehydrated methylene chloride (16 mL). Then,N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 1.15g), 1-hydroxybenzotriazole monohydrate (HOBt.H₂O, 0.918 g), andtriethylamine (1.01 g) were added, followed by stirring for 10 minutes.Benzyl hydrazinecarboxylate (1.66 g) was added, followed by stirring for18 hours. After completion of the reaction, the reaction solution waswashed with 0.5M hydrochloric acid and saturated brine, then the organiclayer was dried over magnesium sulfate, the solvent was distilled offunder reduced pressure, after that, the resulting residue was subjectedto silica gel column chromatography (hexane/ethyl acetate=4/1 0/1→ethylacetate/methanol=30/1) to afford 1.48 g of the title compound (yield81.6%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.64 (m, 1H), 1.87-2.16 (m, 2H),2.38 (m, 1H), 3.31-3.45 (m, 2H), 4.32 (m, 1H), 5.14-5.19 (m, 2H), 6.68(br s, 1H), 7.34-7.40 (m, 5H), 8.76 (br s, 1H); MS m/z 364 [M+H]⁺.

Reference Example 6 (S)-tert-Butyl2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate

(S)-tert-Butyl2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate(1.089 g, 3.00 mmol) described in Reference Example 5 was dissolved inmethanol (15 mL), 10% palladium-carbon (50% water content, 200 mg) wasadded, followed by stirring at room temperature for 1 hour underhydrogen atmosphere. The catalyst of the reaction mixture was filteredthrough Celite and the solvent was concentrated under reduced pressureto afford 595.5 mg of the title compound (yield 86.6%).

¹H NMR (400 MHz, CD₃OD) δ 1.41-1.45 (m, 9H), 1.80-1.99 (m, 3H),2.15-2.22 (m, 1H), 2.26-3.50 (m, 2H), 4.08-4.15 (m, 1H); MS m/z 230[M+H]⁺.

Reference Example 7 tert-Butyl(2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate

tert-Butyl (2-hydroxyethyl)carbamate (1.61 g, 10.0 mmol) was stirredunder an argon atmosphere at room temperature with dehydratedtetrahydrofuran (50 mL). Then, triphenylphosphine (2.75 g) andN-hydroxyphthalimide (Pht-OH, 1.71 g) were added. After the reactionmixture was under ice cooling, diethyl azodicarboxylate (DEAD, 1.82 g)was added dropwise gradually, followed by stirring at room temperaturefor 24 hours. After completion of the reaction, the residue resultingfrom distilling off the solvent under reduced pressure was subjected tosilica gel column chromatography (hexane/ethyl acetate=4/1→1/1) toafford 2.61 g of the title compound (yield 85.2%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 3.40-3.44 (m, 2H), 4.22-4.24 (m,2H), 5.62 (br s, 1H), 7.73-7.85 (m, 4H); MS m/z 307 [M+H]⁺.

Reference Example 8 tert-Butyl(2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate

tert-Butyl (2-bromoethyl)carbamate (5.00 g, 23.5 mmol) was stirred underan argon atmosphere at room temperature with acetonitrile (74 mL). Then,N-hydroxyphthalimide (Pht-OH, 3.83 g) and triethylamine (5.64 g) wereadded, followed by stirring the reaction mixture at 70° C. for 24 hours.After completion of the reaction, the reaction solution wasconcentrated, followed by diluting with ethyl acetate and washing with0.5M hydrochloric acid and saturated sodium bicarbonate aqueoussolution, and the organic layer was dried over magnesium sulfate, to theresidue resulting from distilling off the solvent under reduced pressurewas added ethyl acetate (10 ml), followed by adding hexane, thereby 4.72g of the title compound was afforded (yield 65.7%). The instrumentaldata were consistent with those of the compound of Reference Example 7.

Reference Example 9 tert-Butyl 2-(aminooxy)ethylcarbamate

To a solution of tert-butyl(2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate (1.83 g, 6.00 mmol)described in Reference Example 7 in methylene chloride (11 mL) wasgradually added 9.8M methylamine methanol solution (1.83 mL), followedby stirring for 2 hours. The reaction solution was filtered and thefiltrate was distilled off under reduced pressure, followed byextracting with 0.5M hydrochloric acid (24 mL). To the resulting aqueouslayer were added methylene chloride and 1M sodium hydroxide (18 mL),thereby the target was extracted with ethylene chloride. The resultingorganic layer was dried over magnesium sulfate and the solvent wasdistilled off under reduced pressure. 1.038 g of the title compound wasafforded as the crude product (yield 98%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (m, 9H), 3.35-3.36 (m, 2H), 3.70-3.72 (m,2H), 4.91 (br s, 1H), 5.47 (br s, 2H); MS m/z 177 [M+H]⁺.

Reference Example 10 Benzyl(2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate

Benzyl (2-hydroxyethyl)carbamate (5.857 g, 30.0 mmol) was stirred underan argon atmosphere at room temperature with dehydrated tetrahydrofuran(150 mL). Then, triphenylphosphine (7.90 g) and N-hydroxyphthalimide(Pht-OH, 4.89 g) were added. After the reaction mixture was under icecooling, 2.2M diethyl azodicarboxylate toluene solution (13.7 mL) wasadded dropwise gradually, followed by stirring overnight at roomtemperature. After completion of the reaction, the residue resultingfrom distilling off the solvent under reduced pressure was subjected tosilica gel column chromatography (hexane/ethyl acetate=1/1) to afford9.36 g of the title compound (yield 92%).

¹H NMR (400 MHz, CDCl₃) δ 3.50-3.54 (m, 2H), 4.26-4.34 (m, 2H), 5.14 (brs, 2H), 5.98 (br s, 1H), 7.18-7.40 (m, 5H), 7.75-8.06 (m, 4H); MS m/z358 [M+H]⁺.

Reference Example 11 Benzyl 2-(aminooxy)ethylcarbamate

To a solution of benzyl(2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate (9.36 g, 27.50 mmol)described in Reference Example 10 in methylene chloride (51 mL) wasgradually added 9.8M methylamine methanol solution (8.50 mL), followedby stirring for 2 hours. The reaction solution was distilled off underreduced pressure, and methylene chloride (50 mL) and water (80 mL) wereadded, followed by adjusting to pH 1 with 5M hydrochloric acid, aqueouslayer separation, and further washing with methylene chloride (50 mL).To the resulting aqueous layer was added methylene chloride (50 mL),followed by adjusting to pH 11 with 5M sodium hydroxide, organic layerseparation, and further extracting the aqueous layer with methylenechloride (50 mL) twice. The combined organic layers were washed with 50%potassium carbonate aqueous solution, followed by drying over anhydrouspotassium carbonate, and distilling off the solvent under reducedpressure. The resulting residue was subjected to silica gel columnchromatography (ethyl acetate) to afford 5.61 g of the title compound(yield 97%).

¹H NMR (400 MHz, CDCl₃) δ 3.42-3.46 (m, 2H), 3.72-3.74 (m, 2H), 5.10 (s,2H), 5.15 (br s, 1H), 7.29-7.39 (m, 5H); MS m/z 211 [M+H]⁺.

Reference Example 122-(2-((Triisopropylsilyl)oxy)ethoxy)isoindoline-1,3-dione Step 12-(2-Hydroxyethoxy)isoindoline-1,3-dione

To a solution of N-hydroxyphthalimide (2.20 g, 13.5 mmol) and sodiumacetate (3.30 g) in dimethylsulfoxide (40 mL) was added 2-bromoethanol(2.88 mL) under an argon atmosphere at room temperature. The reactionmixture was stirred at 70° C. for 5 hours, followed by cooling to roomtemperature, adding water (40 mL), and extracting with methylenechloride. The resulting organic layer was washed with water, 2.5Mhydrochloric acid, and saturated brine. The washed organic layer wasdried over magnesium sulfate, the residue resulting from distilling offthe solvent under reduced pressure was recrystallized with ethanol andwater to afford 1.86 g of the title compound (yield 66%).

¹H NMR (400 MHz, CD₃OD) δ 3.84 (t, J=4.6 Hz, 2H), 4.26 (t, J=4.6 Hz,2H), 7.89-7.80 (m, 4H); MS m/z 208 [M+H]⁺.

Step2 2-(2-((Triisopropylsilyl)oxy)ethoxy)isoindoline-1,3-dione

To a solution of 2-(2-hydroxyethoxy)isoindoline-1,3-dione (622 mg, 3.00mmol) in dehydrated methylene chloride (6 mL), imidazole (306 mg) andchlorotriisopropylsilane (TIPSC1, 963 μL) were added under an argonatmosphere at room temperature. After the reaction mixture was stirredat room temperature overnight, 2M hydrochloric acid was added to stopthe reaction, followed by distilling off methylene chloride underreduced pressure. The resulting aqueous layer was extracted with ethylacetate, followed by washing the organic layer with saturated brine andthen drying over magnesium sulfate. The resulting residue was subjectedto silica gel column chromatography (hexane/ethyl acetate=9/1→2/1) toafford 1.04 g of the title compound (yield 95%).

¹H NMR (400 MHz, CDCl₃) δ 0.93-1.06 (m, 21H), 4.09 (t, J=4.8 Hz, 2H),4.33 (t, J=4.8 Hz, 2H), 7.70-7.76 (m, 2H), 7.80-7.86 (m, 2H); MS m/z 364[M+H]⁺.

Reference Example 13 (R)-tert-Butyl3-(aminooxy)pyrrolidine-1-carboxylate

To (R)-tert-butyl3-((1,3-dioxoisoindolin-2-yl)oxy)pyrrolidine-1-carboxylate (2.73 g, 8.21mmol) prepared following a procedure analogous to Reference Example 7from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate in methanol (43mL) was gradually added hydrazine monohydrate (1.54 g), followed bystirring for 2 hours. The reaction solution was filtered, and theresidue resulting from distilling off the filtrate under reducedpressure was subjected to silica gel column chromatography (hexane/ethylacetate=4/1→0/1) to afford 1.30 g of the title compound (yield 78.3%).¹H NMR (400 MHz, CDCl₃) δ 1.45 (m, 9H), 1.86-1.88 (m, 1H), 2.01-2.06 (m,1H), 3.26-3.60 (m, 4H), 4.42 (br s, 1H); MS m/z 203 [M+H]⁺.

Reference Example 14 tert-Butyl4-(2-((1,3-dioxoisoindolin-2-yl)oxy)acetyl)-1,4-diazepine-1-carboxylate

tert-Butyl 1,4-diazepine-1-carboxylate (2.00 g, 10.0 mmol) was stirredunder an argon atmosphere under ice cooling with dehydratedtetrahydrofuran (50 mL). After triethylamine (1.01 g) was added,chloroacetyl chloride (1.01 g) was gradually added. After completion ofthe reaction, N-hydroxyphthalimide (1.95 g) and triethylamine (2.22 g)were added. The reaction mixture was stirred at 60° C. for 22 hours.After completion of the reaction, the reaction solution wasconcentrated, followed by diluting with ethyl acetate, washing with 8%citric acid and saturated sodium bicarbonate aqueous solution, dryingthe organic layer over magnesium sulfate. The residue resulting fromdistilling off the solvent under reduced pressure was subjected tosilica gel column chromatography (hexane/ethyl acetate=4/1→0/1) toafford 3.74 g of the title compound (yield 93.0%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (m, 9H), 1.85-1.99 (m, 2H), 3.37-4.11 (m,8H), 4.84 (br s, 2H), 7.71-7.84 (m, 4H); MS m/z 404 [M+H]⁺.

Reference Example 15 tert-Butyl4-(2-(aminooxy)acetyl)-1,4-diazepine-1-carboxylate

To tert-butyl4-(2-((1,3-dioxoisoindolin-2-yl)oxy)acetyl)-1,4-diazepine-1-carboxylate(2.14 g, 5.30 mmol) described in Reference Example 14 in methanol (16mL) was gradually added 9.8M methylamine methanol solution (1.62 mL),followed by stirring for 2 hours. The residue resulting from thedistilling off the reaction solution under reduced pressure wasdissolved in ethyl acetate (50 ml), followed by extracting with 0.25Mhydrochloric acid (20 mL). To the resulting aqueous layer were addedmethylene chloride and 0.3M sodium hydroxide (40 mL) and the target wasextracted with methylene chloride. The resulting organic layer was driedover magnesium sulfate and the solvent was distilled off under reducedpressure. 1.298 g of the title compound was afforded as the crudeproduct (yield 89.6%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (m, 9H), 1.85-1.99 (m, 2H), 3.36-3.63 (m,8H), 4.37 (m, 2H), 5.92 (br s, 2H); MS m/z 274 [M+H]⁺.

Reference Example 16 tert-Butyl 2-(aminooxy)ethyl (methyl)carbamate

The title compound was prepared from tert-butyl2-hydroxyethyl(methyl)carbamate, following a procedure analogous toReference Example 7 and Reference Example 13.

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 2.88 (br s, 3H), 3.36-3.53 (m,2H), 3.75 (t, J=6.2 Hz, 2H), 5.30-5.75 (m, 2H); MS m/z 191 [M+H]⁺.

Reference Example 17 tert-Butyl (2-(aminooxy)ethyl) (isopropyl)carbamate

The title compound was prepared from tert-butyl2-hydroxyethyl(isopropyl)carbamate, following a procedure analogous toReference Example 7 and Reference Example 15.

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.4 Hz, 6H), 1.47 (s, 9H),3.22-3.44 (m, 2H), 3.72 (t, J=6.4 Hz, 2H), 3.82-4.45 (m, 1H), 5.30-5.71(m, 2H); MS m/z 219 [M+H]⁺.

Reference Example 18 2-(Aminooxy)-N,N-dimethylethanamine dihydrochloride

The title compound was prepared according to J. Med. Chem., 2000, 43(15), pp 2332-2349.

¹H NMR (400 MHz, CDCl₃) δ 2.80 (s, 6H), 3.43 (t, J=4.6Hz, 2H), 4.44 (d,J=4.6 Hz, 2H), 11.2 (br s, 2H); MS m/z 105 [M−2HCl+H]⁺.

Reference Example 19 (S)-tert-Butyl (1-(aminooxy)propan-2-yl)carbamate

The title compound was prepared from (5)-tert-butyl1-hydroxypropan-2-ylcarbamate, following a procedure analogous toReference Example 7 and Reference Example 15.

¹H NMR (400 MHz, CDCl₃) δ 1.12 (d, J=6.8 Hz, 3H), 1.45 (s, 9H),3.43-3.54 (m, 1H), 3.64 (dd, J=11.2, 4.0 Hz, 1H), 4.00 (br s, 1H), 4.64(br s, 1H), 5.57 (br s, 1H), 6.64 (br s, 1H); MS m/z 191 [M+H]⁺.

Reference Example 20 tert-Butyl 3-(aminooxy)propylcarbamate

The title compound was prepared from tert-butyl3-hydroxypropylcarbamate, following a procedure analogous to ReferenceExample 7 and Reference Example 13.

¹H NMR (400 MHz, CDCl₃) δ 1.44 (s, 9H), 1.68-1.82 (m, 2H), 3.14-3.27 (m,2H), 3.73 (t, J=6.0 Hz, 2H), 4.77 (br s, 1H), 5.40 (br s, 2H); MS m/z191 [M+H]⁺.

Reference Example 21 (S)-tert-Butyl2-((aminooxy)methyl)azetidine-1-carboxylate

The title compound was prepared from (5)-tert-butyl2-(hydroxymethyl)azetidine-1-carboxylate, following a procedureanalogous to Reference Example 7 and Reference Example 15.

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.97-2.11 (m, 1H), 2.19-2.30 (m,1H), 3.78-3.93 (m, 4H), 4.42 (br s, 1H), 5.62 (br s, 1H); MS m/z 203[M+H]⁺.

Reference Example 22 (R)-tert-Butyl2-(aminooxymethyl)pyrrolidine-1-carboxylate

The title compound was prepared from (R)-tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate, following a procedureanalogous to Reference Example 7 and Reference Example 13.

¹H NMR (400 MHz, CDCl₃) δ 1.47 (s, 9H), 1.68-1.97 (m, 4H) 3.33 (br s,2H), 3.56 (br s, 1H), 3.61-3.82 (m, 1H), 3.88-4.26 (m, 1H), 5.37-5.74(m, 2H); MS m/z 217 [M+H]⁺.

Reference Example 23 (S)-tert-Butyl2-((aminooxy)methyl)piperidine-1-carboxylate

The title compound was prepared from (5)-tert-butyl2-(hydroxymethyl)piperidine-1-carboxylate, following a procedureanalogous to Reference Example 7 and Reference Example 15.

¹H NMR (400 MHz, CDCl₃) δ 1.32-1.76 (m, 6H), 1.47 (s, 9H), 2.71-2.84 (m,1H), 3.56 (dd, J=11.2, 5.2 Hz, 1H), 3.86-4.04 (m, 2H), 4.59 (br s, 1H),5.64 (br s, 2H); MS m/z 231 [M+H]⁺.

Reference Example 24 (S)-tert-Butyl3-(aminooxy)pyrrolidine-1-carboxylate

(5)-tert-Butyl3-((1,3-dioxoisoindolin-2-yl)oxy)pyrrolidine-1-carboxylate (2.91 g, 8.77mmol) prepared from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylatefollowing a procedure analogous to Reference Example 7 was graduallyadded to methanol (43 mL) and hydrazinemonohydrate (1.54 g), followed bystirring for 3 hours. The reaction solution was filtered and the residueresulting from distilling off the filtrate under reduced pressure wassubjected to silica gel column chromatography (hexane/ethylacetate=4/1→0/1) to afford 1.75 g of the title compound (yield 98.7%).¹H NMR (400 MHz, CDCl₃) δ 1.42 (m, 9H), 1.86 (m, 1H), 2.01-2.06 (m, 1H),3.28-3.60 (m, 4H), 4.23 (br s, 1H); MS m/z 203 [M+H]⁺.

Reference Example 25 tert-Butyl 3-((aminooxy)methyl)azetidine-1-carboxylate

The title compound was prepared from tert-butyl3-(hydroxymethyl)azetidine-1-carboxylate, following a procedureanalogous to Reference Example 7 and Reference Example 15.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H), 2.68-2.90 (m, 1H), 3.57-3.88 (m,4H), 3.88-4.09 (m, 2H), 5.43 (br s, 2H); MS m/z 203 [M+H]⁺.

Example 1 (2S,55)-tert-Butyl 5-hydroxypiperidine-2-carboxylate (2)

To a solution of (2S,5S)-1-benzyl 2-tert-butyl5-hydroxypiperidine-1,2-dicarboxylate (67.2 g) described in ReferenceExample 1M ethanol (900 mL) was added 10% palladium-carbon (watercontent approximately 50%, 10.1 g), followed by vigorously stirringunder an hydrogen atmosphere at room temperature overnight. The catalystof the mixture was filtered through Celite, followed by concentratingthe filtrate, thereby 39.3 g of the title compound was afforded as thecolorless solid (yield 97%). Enantiomeric excess 99% ee or more(CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm,diethylamine/hexane/ethanol=0.1/80/20, flow rate 1 mL/min., retentiontime 6.3 min.).

[α]²⁰ _(D)−28.7° (c 1.01, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.47 (s,9H), 1.63 (m, 1H), 1.79-1.84 (m, 3H), 2.82 (dd, J=12.2, 2.2 Hz, 1H),3.02 (ddd, J=12.2, 3.7, 1.7 Hz, 1H), 3.21 (m, 1H), 3.80 (m, 1H); MS m/z202 [M+H]⁺.

Example 2 (2S,55)-tert-Butyl5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (3)

A solution of (25,55)-tert-butyl 5-hydroxypiperidine-2-carboxylate(39.14 g, 194 mmol) in dehydrated tetrahydrofuran (450 mL) was cooled toa temperature between −3 and −5° C. under an argon atmosphere, followedby adding triethylamine (78.7 g) and adding dropwise trifluoroaceticanhydride (81.5 g) over 30 minutes. The reaction mixture was allowed toreact at a temperature between −3 and −5° C. for 1 hour, followed byadding water (90 mL), raising the temperature to room temperature, andstirring for 1 hour. To the reaction mixture was added water (740 mL),followed by extracting with ethyl acetate (450 mL x three times) andwashing the combined organic layers with 5% citric acid aqueous solution(450 mL), 6.5% sodium bicarbonate aqueous solution (450 mL) and water(450 mL) sequentially. The residue resulting from distilling off thesolvent under reduced pressure was subjected to silica gel columnchromatography (hexane/ethyl acetate=2/1) to afford 50.06 g of the titlecompound as a pale yellow solid (yield 87%). Enantiomeric excess 99% eeor more (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm, hexane/ethanol=4/1, flowrate 1 mL/min., retention time 4.2 min).

[α]²⁰ _(D)−54.1° (c 0.73, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ observed asa mixture of 2 rotamers (7:3). 1.26-1.43 (m, 1H), 1.46 (s, 2.7H), 1.47(s, 6.3H), 1.68-1.77 (m, 1H), 1.81 (d, J=4.8 Hz, 0.3H), 1.89 (d, J=5.2Hz, 0.7H), 2.05-2.08 (m, 1H), 2.36-2.42 (m, 1H), 2.77 (dd, J=12.2, 12.0Hz, 0.3H), 3.12 (dd, J=13.2, 10.7 Hz, 0.7H), 3.68-3.77 (m, 1H), 4.00 (m,1H), 4.52-4.60 (m, 0.6H), 5.07 (d, J=5.9 Hz, 0.7H); MS m/z 298 [M+H]⁺.

Example 3 (2S,5R)-tert-Butyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(IV)

A solution of (2S,5S)-tert-butyl5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (10.22 g,34.38 mmol) in dehydrated acetonitrile (113 mL) was cooled to atemperature between −30 and −40° C. under an argon atmosphere, followedby adding 2,6-lutidine (4.4 mL), then adding dropwisetrifluoromethanesulfonic anhydride (5.92 mL) over 10 minutes, andfurther reacting at −30° C. for 15 minutes. To this reaction mixture wasadded benzyloxyamine (8.46g) (washed with acetonitrile (5 mL)), followedby raising the temperature to 0° C. within 30 minutes, further adding2,6-lutidine (4.4 mL), and allowing to react at a temperature between 0and 5° C. for 3.5 days. This reaction mixture was concentrated underreduced pressure, the resulting residue was diluted with ethyl acetate(200 mL), followed by washing with water (200 mL), 10% citric acidaqueous solution (200 mL×three times), 6.5% sodium bicarbonate aqueoussolution (100 mL), and saturated brine (100 mL) sequentially. Eachaqueous layer was back-extracted with ethyl acetate (100 mL), theorganic layers were combined and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The resultingresidue was subjected to silica gel column chromatography (hexane/ethylacetate=4/1) to afford 11.69 g of the title compound as a colorless oil(yield 85%). Enantiomeric excess 99.0% ee (CHIRALPAK AD-H, 4.6×150 mm,UV 210 nm, hexane/ethanol=9/1, flow rate 1 mL/min, retention time 4.5min.).

[α]²⁰ _(D)−45.6° (c 0.73, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ observed asa mixture of 2 rotamers (7:3). 1.46 (s, 2.7H), 1.48 (s, 6.3H), 1.62-1.65(m, 2H), 1.93-2.05 (m, 2H), 3.13 (m, 0.3H), 3.24-3.29 (m, 1H), 3.46 (m,0.7H), 4.12 (m, 0.3H), 4.58-4.77 (m, 2.7H), 5.06 (m, 0.7H), 5.38 (m,1H), 7.30-7.36 (m, 5H); MS m/z 403 [M+H]⁺.

Example 4 (2S,5R)-tert-Butyl 5-(benzyloxyamino)piperidine-2-carboxylate(4a)

To a solution of (2S,5R)-tert-butyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(6.91 g, 17.17 mmol) in 1,4-dioxane (34 mL) was added water (9.2 mL),followed by adding dropwise 2.5M sodium hydroxide (13.7 mL) underice-cooling, and allowing to react at the same temperature for 0.5hours. To the reaction mixture was added acetic acid (approximately 1mL), followed by concentrating under reduced pressure, and the resultingconcentrated residue was extracted with ethyl acetate (58 mL, 29 mL).Each organic layer was washed with 50% potassium carbonate aqueoussolution, and the combined organic layers were dehydrated over anhydroussodium sulfate to distill off the solvent under reduced pressure. Theresulting residue was subjected to silica gel column chromatography(hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=19/1) to afford4.74 g of the title compound as a colorless oil (yield 90%).Enantiomeric excess 98.9% ee (CHIRALPAK AD-H, 4.6×150 mm, UV 210 nm,diethylamine/hexane/ethanol=0.1/80/20, flow rate 1 mL/min., retentiontime 5.5 min.).

[α]²⁰ _(D)−2.8° (c 0.73, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.28 (m, 1H,1.42-1.46 (m, 10H), 1.92 (m, 1H), 2.04 (ddd, J=12.9, 7.3, 4.0 Hz, 1H),2.43 (dd, J=12.0, 9.8 Hz, 1H), 2.98 (m, 1H), 3.16 (dd, J=11.0, 3.2 Hz,1H), 3.57 (ddd, J=12.0, 4.2, 2.0 Hz, 1H), 4.68 (s, 2H), 7.29-7.35 (m,5H); MS m/z 307 [M+H]⁺.

Example 5 Sequential synthesis of (2S,5R)-tert-Butyl5-(benzyloxyamino)piperidine-2-carboxylate (4a)

A solution of (2S,5S)-tert-butyl5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (47.9 g, 161mmol) in dehydrated acetonitrile (318 mL) was cooled to a temperaturebetween −30 and −40° C. under an argon atmosphere, followed by adding2,6-lutidine (20.5 mL), then adding dropwise trifluoromethanesulfonicanhydride (28.4 mL) over 40 minutes, and further allowing to react at-30° C. for 15 minutes. To this reaction mixture was addedbenzyloxyamine (39.7 g) (washed with acetonitrile (11 mL)) within 8minutes, followed by raising the temperature to 0° C. within 30 minutes,further adding 2,6-lutidine (20.5 mL), and allowing to react at atemperature between 0 and 5° C. for 2 days. This reaction mixture wasconcentrated under reduced pressure, the resulting residue was dilutedwith ethyl acetate (960 mL), and washing with water (960 mL), 10% citricacid aqueous solution (960 mL×three times), 6.5% sodium bicarbonateaqueous solution (480 mL) and saturated brine (480 mL) sequentially.Each aqueous layer was back-extracted with ethyl acetate (960 mL), theorganic layers were combined, and the solvent was distilled off underreduced pressure. The resulting residue was dissolved in 1,4-dioxanesolution (320 mL) and water (86 mL), followed by adding dropwise 2.5Msodium hydroxide (128 mL) under ice-cooling, and allowing to react atthe same temperature for 0.5 hours. To the reaction mixture was addedacetic acid (approximately 9.3 mL), followed by concentrating underreduced pressure, the resulting concentrated residue was extracted withethyl acetate (580 mL, 290 mL). Each organic layer was washed with 50%potassium carbonate aqueous solution (580 mL), followed by combining theorganic layers and the solvent was distilled off under reduced pressure.The resulting residue was subjected to silica gel column chromatography(hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=100/1→19/1) toafford 36.58 g of the title compound as a colorless oil (yield 74%).Instrumental data were consistent with those of Example 4.

Example 6 (2S,5R)-tert-Butyl6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (5a)

To a solution of (2S,5R)-tert-butyl5-(benzyloxyamino)piperidine-2-carboxylate (4.14 g, 13.51 mmol) indehydrated acetonitrile (615 mL) was added triethylamine (4.9 mL) underan argon atmosphere at 0° C., followed by adding dropwise diphosgene(1.18 mL) for 5 minutes, and stirring at the same temperature for10minutes. To this solution was added 4-dimethylaminopyridine (182 mg),followed by raising the temperature to room temperature and allowing toreact for 3 hours. The reaction mixture was concentrated under reducedpressure to the volume of one tenth thereof, the resulting concentratedsolution was diluted with ethyl acetate, followed by washing with water,5% citric acid aqueous solution, 6.5% sodium bicarbonate aqueoussolution, and saturated brine sequentially, then drying over anhydrousmagnesium sulfate, and distilling off the solvent under reducedpressure. The resulting residue was subjected to silica gel columnchromatography (hexane/ethyl acetate=2/1) to afford 3.09 g of the titlecompound (yield 69%). The resulting solid was recrystallized from ethylacetate-hexane, the generated precipitate was filtered off. The wetcrystal was washed with hexane, followed by drying at room temperatureunder reduced pressure, and the title compound was afforded as acolorless crystalline powder. Enantiomeric excess 99.4% ee (CHIRALPAKAD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min.,retention time 8.0 min.).

Mp 83°; [α]²⁰ _(D)+5.9° (c 0.61, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.48(s, 9H), 1.62 (m, 1H), 2.00-2.10 (m, 3H), 2.98 (d, J=11.7 Hz, 1H), 3.03(m, 1H), 3.30 (m, 1H), 4.01 (m, 1H), 4.90 (d, J=11.5 Hz, 1H), 5.06 (d,J=11.5 Hz, 1H), 7.35-7.42 (m, 5H); MS m/z 333 [M+H]⁺.

In powder X-ray diffraction diagram, the crystal of the title compounddemonstrated characteristic peak patterns as shown in the followingTable 1. For measurement, RINT 2100 from Rigaku Corporation was used asa powder X-ray diffraction device, in which measurement was conductedwith CuKα1 as an X-ray source, a tube voltage of 40 kV, a tube currentof 40 mA, a scan speed of 4°/min., and a scan range of 2θ=3 to 40°.

TABLE 1 Powder X-ray Diffraction of Compound (5a) Peak Position 2θLattice spacing (d) Relative Intensity (Cuka) Å I/IO 7.64 11.56 13 8.0610.96 67 13.50 6.55 46 14.74 6.00 15 15.30 5.79 11 15.92 5.56 44 16.185.47 58 16.86 5.25 64 18.10 4.90 46 20.38 4.35 18 20.96 4.23 100 23.043.86 10

Example 7 (2S,5R)-tert-Butyl6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (5a):Reaction by Phosgene Gas

To a solution of (2S,5R)-tert-butyl5-(benzyloxyamino)piperidine-2-carboxylate (3.0 g, 9.791 mmol) indehydrated acetonitrile (150 mL), under an argon atmosphere, at roomtemperature, were added triethylamine (3.82 mL) and4-dimethylaminopyridine (120 mg), and phosgene gas (generated by addingdiphosgene (1.548 g) dropwise on the activated carbon (1 g) warmed to60° C. within 1.5 hours) was introduced by means of an argon stream,followed by stirring overnight. Excess phosgene was decomposed withconcentrated ammonia water (0.6 mL), and the solvent of the reactionmixture was concentrated under reduced pressure. The residue was dilutedwith ethyl acetate (50 mL), washed sequentially with water (50 mL), 5%citric acid aqueous solution (50 mL), 6.5% sodium bicarbonate aqueoussolution (25 mL), and saturated brine, then dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The resulting residue was subjected to silica gel columnchromatography (hexane/ethyl acetate=2/1) to afford 2.25 g of the titlecompound (yield 69%). The resulting solid was recrystallized from ethylacetate-hexane, the generated precipitate was filtered off. The wetcrystal was washed with hexane and subsequently dried under reducedpressure at room temperature to afford the title compound as a colorlesscrystalline powder. Instrumental data were consistent with those of thetitle compound of Example 6.

Example 8(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid cyclohexylamine Salt (6a)

To a solution of (2S,5R)-tert-butyl6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (270 mg,0.842 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid(2 mL) under an argon atmosphere at 0° C., and the temperature wasraised to room temperature, followed by allowing to react for 4 hours.The reaction mixture was concentrated, and the resulting residue wasdiluted with ethyl acetate, washed with water and saturated brinesequentially, dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The resulting residue wasdissolved in ethyl acetate (2.5 mL), and then a solution ofcyclohexylamine (149 mg) in diethyl ether was added at room temperature,followed by stirring at 0° C. for 1 hour. The generated precipitate wasfiltered off, and the filter cake was washed with diethyl ether,followed by drying at room temperature under reduced pressure, and 270mg of the title compound was afforded as a colorless crystalline powder(yield 86%).

Mp 175°; [α]²⁰ _(D)−36.8° (c 0.50, H₂O); ¹H NMR (400 MHz,dimethylsulfoxide-d6) δ 1.00-1.30 (m, 5H), 1.53-1.95 (m, 8H), 2.04-2.09(m, 1H), 2.76 (d, J=11.6 Hz, 1H), 2.80-2.93 (m, 1H), 3.19 (d, J=11.2 Hz,1H), 3.33 (br s, 2H), 3.40 (d, J=7.2 Hz, 1H), 3.51 (br s, 1H), 4.87 (d,J=11.6 Hz, 1H), 4.93 (d, J=11.6 Hz, 1H), 7.30-7.45 (m, 5H), 8.04 (br s,1H); MS m/z 100, 277 [M−C₆H₁₃N+H]⁺.

In powder X-ray diffraction diagram, the crystal of the title compounddemonstrated characteristic peak patterns as shown in the followingTable 2. For measurement, RINT 2100 from Rigaku Corporation was used asa powder X-ray diffraction device, in which measurement was conductedwith CuKα1 as an X-ray source, a tube voltage of 40 kV, a tube currentof 40 mA, a scan speed of 4°/min., and a scan range of 2θ=3 to 40°.

TABLE 2 Powder X-ray Diffraction of Compound (6a) Peak Position 2θLattice spacing (d) Relative Intensity (Cuka) Å I/IO 8.88 9.95 46 10.468.45 9 14.14 6.26 14 15.08 5.87 17 16.04 5.52 100 16.98 5.22 71 17.385.10 17 17.88 4.96 26 18.74 4.73 57 19.52 4.54 22 21.36 4.16 13 22.603.93 68 25.08 3.55 12

Example 9(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (6b)

Cyclohexylamine salt (230 mg) of(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid was dissolved in saturated aqueous sodium dihydrogen phosphatesolution, followed by extraction 4 times with ethyl acetate, and thecombined organic layers were washed with saturated brine, andsubsequently dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and dried under vacuum, to afford161 mg of the title compound as a colorless foamy solid (yield 87%).Enantiomeric excess 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm,trifluoroacetic acid/hexane/ethanol=0.1/80/20, UV 210 nm, flow rate 1mL/min., retention time 10.5min.).

[α]²⁰ _(D)+11.5° (c 0.56, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.67 (m,1H), 2.04-2.26 (m, 3H), 2.85 (d, J=12.0 Hz, 1H), 3.13 (m, 1H), 3.35 (m,1H), 4.12 (m, 1H), 4.91 (d, J=11.3 Hz, 1H), 5.06 (d, J=11.3 Hz, 1H),7.37-7.44 (m, 5H); MS m/z 277 [M+H]⁺.

Example 10(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (6b); Treatment with Diluted Hydrochloric Acid Followed byCrystallization

(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid cyclohexylamine salt (3.75 g, 10.0 mmol) was dissolved in water (50ml). Ethyl acetate (100 mL) and 1M hydrochloric acid (20 mL) were added.The mixture was stirred, followed by extracting with ethyl acetate (100mL each time) three times. The organic layer was dried over anhydrousmagnesium sulfate, the solvent was concentrated to 10 mL under reducedpressure. 120 mL of hexane was gradually added while stirring underice-cooling and the resulting precipitate was filtered off. Thegenerated precipitate was filtered off. After the wet crystal was washedwith hexane, and dried at room temperature under reduced pressure toafford 2.44 g of the title compound as a colorless crystalline powder.Mp 116° C.; the other instrumental data were consistent with those ofthe title compound of Example 9.

In powder X-ray diffraction diagram, the crystal of the title compounddemonstrated characteristic peak patterns as shown in the followingTable 3. For measurement, RINT 2100 from Rigaku Corporation was used asa powder X-ray diffraction device, in which measurement was conductedwith CuKα1 as an X-ray source, a tube voltage of 40 kV, a tube currentof 40 mA, a scan speed of 4°/min., and a scan range of 2θ=3 to 40°.

TABLE 3 Powder X-ray diffraction of compound (6b) Peak Position 2 θLattice spacing (d) Relative Intensity (Cuka) Å I/IO 10.80 8.19 10 12.387.14 14 13.32 6.64 11 14.06 6.29 81 15.82 5.60 33 17.02 5.21 92 18.044.91 12 19.28 4.60 37 21.06 4.21 100 24.08 3.69 42 25.80 3.45 16 28.523.13 33

Example 11 Dihydrochloride of (2 S, 5R)-5-(benzyloxyamino)piperidine-2-carboxylic acid (IV-a 1)

To 5M hydrochloric acid (500 mL) was added (2S,5R)-tert-butyl5-(benzyloxyamino)piperidine-2-carboxylate (46.69 g), followed bystirring at 65° C. for 2 hours. The reaction solution was cooled to roomtemperature, the residue resulting from concentrating the solvent underreduced pressure was dissolved in water (500 mL), followed by addingactivated carbon (2.7 g) and stirring for 30 minutes. The activatedcarbon was removed by filtration, the filtrate was concentrated todryness, followed by drying under vacuum overnight, and thereby 49.3 gof the title compound was afforded as a pale yellow solid(quantitative).

¹H NMR (400 MHz, D₂O) δ 1.39-1.49 (m, 1H), 1.59-1.70 (m, 1H), 1.88-1.95(m, 1H), 2.20-2.28 (m, 1H), 2.78 (t, J=11.8 Hz, 1H), 3.19-3.28 (m, 1H),3.48-3.52 (m, 1H), 3.68-3.72 (m, 1H), 3.57 (s, 3H), 3.70 (dd, J=3.4,12.6 Hz), 4.68 (s, 2H), 7.26-7.32 (m, 5H); MS m/z 251 [M−2HCl+H]⁺.

Example 12 Dihydrochloride of (2S,5R)-methyl5-(benzyloxyamino)piperidine-2-carboxylate (4b)

To 2M hydrogen chloride methanol (7 mL) was added(2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylic acid dihydrochloride(176 mg), followed by refluxing for 3 hours, the reaction solution wasconcentrated under reduced pressure, dried under vacuum overnight toafford the title compound as a pale yellow solid (quantitative).

¹H NMR (400 MHz, D₂O) δ 1.40-1.51 (m, 1H), 1.61-1.72 (m, 1H), 1.90-1.94(m, 1H), 2.25-2.30 (m, 1H), 2.80 (t, J=11.2 Hz, 1H), 3.19-3.27 (m, 1H),3.51-3.55 (m, 1H), 3.66 (s, 3H), 3.87-3.91 (m, 1H), 4.68 (s, 2H), 7.27(s, 5H); MS m/z 265 [M−2HCl+H]⁺.

Example 13 (2S,5R)-Methyl 5-(benzyloxyamino)piperidine-2-carboxylate(4b)

To (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate,dihydrochloride (1.319 g) were added ethyl acetate (20 mL) and 50%potassium carbonate aqueous solution (20 mL) for liquid separation andthe aqueous layer was extracted with ethyl acetate (15 mL) three times.The organic layer was washed with saturated brine, dried over anhydroussodium sulfate, and filtered, subsequently concentrated under reducedpressure, and dried under vacuum overnight to afford 975 mg of the titlecompound (yield 94%).

¹H NMR (400 MHz, CDCl₃) δ 1.25-1.35 (m, 1H), 1.49-1.59 (m, 1H),1.89-2.11 (m, 2H), 2.45 (t, J=11.7 Hz, 1H), 2.96-3.03 (m, 1H), 3.28-3.92(m, 2H), 3.72 (s, 3H), 4.68 (s, 2H), 7.26-7.35 (m, 5H); MS m/z 265[M+H]⁺.

Example 14 Direct Synthesis of Dihydrochloride of (2S,5R)-methyl5-(benzyloxyamino)piperidine-2-carboxylate (4b)

The crude material (507 mg, 1.26 mmol) of (2S,5R)-tert-butyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylatedescribed in Example 3 was dissolved in 2M hydrogen chloride methanolsolution (10.3 mL), followed by refluxing for 33 hours. The reactionmixture was concentrated under reduced pressure to the volume ofapproximately 3.6 mL, and ethyl acetate (10.3 mL) was added to theconcentrated solution to allow precipitating. The resulting precipitatewas collected by suction filtration, the filter cake was washed with asmall amount of ethyl acetate, followed by through-flow drying, andthereby 290 mg of the title compound was afforded as a white powder(yield 68%). The instrumental data were consistent with those of Example12.

Example 15 (2S,5R)-Methyl6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (5b)

To (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate (1.154 g,4.37 mmol) was added dehydrated acetonitrile (198 mL), followed byice-cooling. Triethylamine (1.60 mL) and diphosgene (0.389 mL) weresequentially added dropwise at 5° C. or less, followed by stirring at 2°C. for 20 minutes. Then, to the reaction solution was added4-dimethylaminopyridine (70.0 mg), followed by stirring at roomtemperature for 10 hours. The reaction solution was concentrated underreduced pressure, followed by substituting and concentrating with ethylacetate three times, and the solution was concentrated to 30 mL. Ethylacetate (20 mL) and water (40 mL) were added thereto, followed by liquidseparation, and the separated aqueous layer was extracted with ethylacetate (30 mL) twice. The combined organic layers were washed with 5%citric acid aqueous solution (40 mL), 6.5% sodium bicarbonate aqueoussolution (30 mL), and 5% brine (30 mL), and dried over anhydrous sodiumsulfate, followed by filtration and concentration under reducedpressure. 1.16 g of the resulting residue was diluted with ethyl acetate(5.5 mL), and n-hexane (11 mL) was added, and a seed crystal wasinoculated for crystallization. Further, n-hexane (49 mL) was added,followed by stirring at 0° C. for 1 hour. Subsequently, crystals werefiltered, washed with n-hexane (60 mL), and then dried under vacuum toafford 882.3 mg of the title compound as colorless crystalline powder(yield 71%).

Mp 86°; [α]²⁰ _(D)+5.3° (c 1.10, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ1.65-1.70 (m, 1H), 2.03-2.12 (m, 3H), 2.90 (d, J=12.0 Hz, 1H), 3.07 (m,1H), 3.79 (s, 3H), 4.12 (dd, J=4.6, 4.4 Hz, 1H), 4.91 (d, J=11.2 Hz,1H), 5.06 (d, J=11.2 Hz, 1H), 7.35-7.44 (m, 5H); MS m/z 291 [M+H]⁺.

In powder X-ray diffraction diagram, the crystal of the title compounddemonstrated characteristic peak patterns as shown in the followingTable 4. For measurement, RINT 2100 from Rigaku Corporation was used asa powder X-ray diffraction device, in which measurement was conductedwith CuKα1 as an X-ray source, a tube voltage of 40 kV, a tube currentof 40 mA, a scan speed of 4°/min., and a scan range of 2θ=3 to 40°.

TABLE 4 Powder X-ray Diffraction of Compound (5b) Peak Position 2 θLattice spacing (d) Relative Intensity (Cuka) Å I/IO 8.50 10.39 92 15.105.86 9 15.56 5.69 66 16.60 5.34 11 18.42 4.81 28 19.98 4.44 100 22.303.98 9 23.50 3.78 66 28.64 3.11 13 29.44 3.03 19 30.52 2.93 13 32.282.77 11

Example 16(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (6b): Synthesis from (5b)

To (2S,5R)-methyl6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (809.0mg, 2.79 mmol) were added tetrahydrofuran (8 mL) and water (3.6 mL),then 0.5M lithium hydroxide aqueous solution (6.41 mL) was addeddropwise at 4.9° C. or less over 10 minutes. The reaction solution wasstirred at 2° C. for 2 hours, followed by adding water (30 mL) andwashing with ethyl acetate (25 mL). To the separated aqueous layer wasadded ethyl acetate (15 mL), the aqueous layer was adjusted to pH 4.0with 1M hydrochloric acid aqueous solution, and extracted with ethylacetate twice (ethyl acetate: total volume of 65 mL). The separatedaqueous layer was adjusted to pH3.4 with 1M hydrochloric acid aqueoussolution, and extracted with ethyl acetate once, subsequently theaqueous layer was adjusted to pH 2.4 and extracted with ethyl acetatetwice. The resulting extraction liquid from a total of five extractionswith ethyl acetate (175 mL) was washed with saturated brine (40 mL),dried over anhydrous sodium sulfate, filtrated, and then concentratedunder reduced pressure. 759.1 mg of the resulting residue was dilutedwith ethyl acetate (5 mL), and n-hexane (3 mL) was added, and a seedcrystal was inoculated for crystallization. Further, ethylacetate/n-hexane (5/3) solution (8 mL) was added and stirred,subsequently n-hexane (20 mL) was added and stirred at 4° C. for 14hours. The crystals were filtered, followed by washing with n-hexane (55mL), subsequently drying under vacuum to afford 633.6 mg of the titlecompound as a colorless crystalline powder (yield 82%). The instrumentaldata of this were consistent with those of the compound of Example 9.

Example 17(2S,5R)-7-Oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

To a solution of the carboxylic acid (6b, 371 mg, 1.34 mmol) of Example9 or 16 in tetrahydrofuran (7 mL) were added triethylamine (0.227 mL)and isobutyl chloroformate (218 μl) under ice-cooling, followed bystirring at 0° C. for 15 minutes. To the reaction solution was addedt-butyl carbazate (245 mg) at 0° C., followed by stirring at roomtemperature for 1.5 hours, and then concentrating under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1-0/1) to afford 583 mg of thetitle compound (yield 98%).

[α]_(D) ²⁰+54.3° (c 0.56, CHCl₃); ¹H NMR (400 MHz, CDCl₃) 6 1.47 (s,9H), 1.56-1.67 (m, 1H), 1.90-2.05 (m, 2H), 2.34-2.41 (m, 1H), 3.04-3.17(m, 2H), 3.26-3.31 (m, 1H), 4.00 (d, J=7.6 Hz, 1H), 4.91 (d, J=11.2 Hz,1H), 5.06 (d, J=11.2 Hz, 1H), 6.31 (br s, 1H), 7.34-7.46 (m, 5H), 8.14(d, J=2.8 Hz, 1H); MS m/z 391 [M+H]⁺.

Step 2 tert-Butyl2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

The compound (573 mg, 1.47 mmol) of the above Step 1 was dissolved inmethanol (10 mL), and 10% palladium-carbon (50% water content, 126 mg)was added, followed by stirring under hydrogen atmosphere at roomtemperature for 55 minutes. The catalyst of the reaction mixture wasfiltered through Celite, the solvent was concentrated under reducedpressure to afford 423 mg of the title compound (yield 96%).

¹H NMR (400 MHz, CD₃OD) δ 1.48 (s, 9H), 1.70-1.82 (m, 1H), 1.86-1.98 (m,1H), 2.01-2.12 (m, 1H), 2.27 (br dd, J=14.6, 6.6 Hz, 1H), 3.11-3.25 (m,2H), 3.70 (br s, 1H), 3.91 (br d, J=7.2 Hz, 1H); MS m/z 301 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the compound (421 mg, 1.40 mmol) of the above Step 2 inpyridine (10 mL) was added sulfur trioxide-pyridine complex (1.01 g),followed by agitating at room temperature overnight. To the reactionsolution was added methylene chloride, after filtration, followed byconcentrating under reduced pressure, and adjusting to pH 8 withhalf-saturated sodium bicarbonate aqueous solution. The aqueous layerwas washed with methylene chloride. Subsequently, to the aqueous layerwere added tetrabutylammonium hydrogen sulfate (564 mg) and methylenechloride, followed by agitating for 15 minutes. The aqueous layer wasextracted with methylene chloride, subsequently the resulting organiclayer was dried over anhydrous sodium sulfate, after filtration,followed by concentrating under reduced pressure to afford 841 mg oftetrabutylammonium tert-butyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 12H), 1.40-1.53 (m, 8H),1.49 (s, 9H), 1.60-1.75 (m, 9H), 1.84-1.98 (m, 1H), 2.15-2.24 (m, 1H),2.35-2.44 (m, 1H), 3.06-3.18 (m, 1H), 3.24-3.36 (m, 8H), 3.39 (br d,J=11.6 Hz, 1H), 3.97 (br d, J=7.2 Hz, 1H), 4.36 (br s, 1H), 6.31 (br s,1H), 8.59-8.67 (m, 1H); MS m/z 381 [M−Bu₄N+2H]⁺.

All the amount of the above tetrabutylammonium salt was dissolved inmethylene chloride (15 mL), followed by adding trifluoroacetic acid (5mL) and stirring at room temperature for 1 hour. Subsequently, thereaction solution was concentrated under reduced pressure, the resultingresidue was washed with diethyl ether and dried. The resulting crudeproduct was adjusted to pH 8 with sodium bicarbonate aqueous solutionand subjected to octadecyl silica gel column chromatography to afford227 mg of the title compound (2 steps, yield 58%). [α]_(D) ²⁰−52.9° (c0.15, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.63-1.73 (m, 1H), 1.76-1.87 (m,1H), 1.90-1.99 (m, 1H), 2.00-2.09 (m, 1H), 2.97 (d, J=12.2 Hz, 1H), 3.17(br d, J=12.2 Hz, 1H), 3.92 (d, J=7.2 Hz, 1H), 4.04-4.08 (m, 1H); MS m/z281 [M+H]⁺.

Example 18 Sodium tert-butyl1-methyl-2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylateStep 1 tert-Butyl2-{[(2SR,5RS)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate

To a solution of(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (400 mg, 1.45 mmol) and tert-butyl 1-methylhydrazinecarboxylate(232 mg) in tetrahydrofuran (14 mL) were added triethylamine (972 μL)and 2-chloro-1-methylpyridin-1-ium iodide (554 mg), followed by stirringat room temperature overnight. To the reaction solution was addedsaturated sodium bicarbonate aqueous solution, followed by extractingwith chloroform. The organic layer was dried over sodium sulfate, andthen concentrated. The resulting crude product was purified by silicagel column chromatography to afford 458 mg of the title compound (yield78%).

¹H NMR (400 MHz, CDCl₃) δ 1.29-1.40 (m, 10H), 1.53-1.60 (m, 2H),2.24-2.30 (m, 1H), 2.96-3.24 (m, 6H), 3.87 (d, J=1.7, 1H), 4.83 (d,J=2.8, 1H), 4.97 (d, J=2.8, 1H), 7.26-7.36 (m, 5H).

Step 2 tert-Butyl2-{[(2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylate

To a solution of the compound (485 mg, 1.20 mmol) of the above Step 1 inmethanol (14 mL) was added 50% palladium-carbon (50% water content, 50mg), followed by stirring under hydrogen atmosphere at room temperaturefor 2 hours. The catalyst in the reaction mixture was filtered offthrough PTFE membrane, followed by concentrating under reduced pressure.The resulting crude product was purified by silica gel columnchromatography to afford 359 mg of the title compound (yield 95%).

MS m/z 315 [M+H]⁺.

Step 3 Sodium tert-butyl1-methyl-2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

To a solution of all the amount of the compound of the above Step 2 inmethylene chloride (10.0 mL) were added 2,6-lutidine (842 μL) and sulfurtrioxide-pyridine complex (273 mg), followed by agitating at roomtemperature overnight. To the reaction solution was added chloroform,followed by liquid separation with water. The resulting pyridiniumtert-butyl2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-1-methylhydrazinecarboxylateobtained in the aqueous layer was neutralized with saturated sodiumbicarbonate aqueous solution, and purified by octadecyl silica gelcolumn chromatography to afford 114 mg of the title compound (yield23%).

¹H NMR (400 MHz, D₂O) δ 1.47 (s, 9H), 1.84 (m, 1H), 1.96-2.04 (m, 1H),2.11-2.15 (m, 1H), 2.23-2.28 (m, 1H), 3.11 (s, 3H), 3.18 (d, J=3.0, 1H),3.41 (d, J=2.7, 1H), 4.15 (d, J=1.9, 1H), 4.25 (br s, 1H); MS m/z 393[M−Na]⁻.

Example 19(2SR,5RS)-N′-Methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Sodium tert-butyl1-methyl-2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate(100 mg, 0.24 mmol) of Example 18 was deprotected with trifluoroaceticacid, and purified by octadecyl silica gel column chromatography toafford 41 mg of the title compound (yield 58%).

¹H NMR (400 MHz, D₂O) δ 1.63-1.71 (m, 1H), 1.74-1.84 (m, 1H), 1.90-1.96(m, 1H), 2.00-2.06 (m, 1H), 3.40 (s, 3H), 2.95 (d, J=3.0, 1H), 3.15 (d,J=3.0, 1H), 3.89 (d, J=1.6, 1H), 4.04 (br s, 1H), MS m/z 293 [M−H]⁻.

Example 20 Sodium(2SR,5RS)-N′,N′-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2SR,5RS)-6-Benzyloxy-N′,N′-dimethyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 18, from(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (200 mg, 0.72 mmol) and 1,1-dimethylhydrazine (48 mg), 150 mg ofthe title compound was afforded (yield 65%).

¹H NMR (400 MHz, CDCl₃) δ 1.53 (m, 1H), 1.75-1.88 (m, 2H), 2.21-2.27 (m,1H), 2.46 (s, 6H), 2.61 (d, J=2.6, 1H), 2.89 (d, J=2.6, 1H), 3.19-3.21(m, 1H), 3.75 (d, J=1.9, 1H), 4.78 (d, J=2.9, 1H), 4.92 (d, J=2.9, 1H),7.16-7.31 (m, 5H).

Step 2(2SR,5RS)-N′,N′-dimethyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 101 mg of the title compound wasafforded (yield 94%).

MS m/z 229 [M+H]⁺.

Step 3 Sodium(2SR,5RS)-N′,N′-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 18, pyridinium(2SR,5RS)-N′,N′-dimethyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideobtained from all the amount of the compound of the above Step 2 wasneutralized with saturated sodium bicarbonate aqueous solution, andpurified by octadecyl silica gel column chromatography to afford 65 mgof the title compound (yield 44%).

¹H NMR (400 MHz, D₂O) δ 1.80-1.98 (m, 2H), 2.07-2.20 (m, 2H), 2.59 (s,6H), 3.11 (d, J=3.0, 1H), 3.33 (d, J=3.0, 1H), 4.01 (d, J=1.3, 1H), 4.22(br s, 1H); MS m/z 307 [M−Na]⁻.

Example 21 Sodium(2S,5R)—N′-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)—N′-acetyl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the carboxylic acid (6b, 2.37 g, 8.57 mmol) of Example9 or 16 in tetrahydrofuran (50 mL) were added triethylamine (1.39 mL)and isobutyl chloroformate (1.32 mL) under ice-cooling, followed byagitating at 0° C. for 20 minutes. To the reaction solution was addedacetohydrazide (807 mg) at 0° C., stirred at room temperature for 40minutes and concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (hexane/ethylacetate=9/1) to afford 2.61 g of the title compound (yield 92%).

[α]_(D) ²⁰+92.3° (c 0.65, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.57-1.70(m, 1H), 1.90-2.15 (m, 2H), 2.06 (s, 3H), 2.30-2.39 (m, 1H), 3.08 (br d,J=12.0 Hz, 1H), 3.13 (d, J=12.0 Hz, 1H), 3.31-3.37 (m, 1H), 4.02 (d,J=7.6 Hz, 1H), 4.92 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz, 1H),7.33-7.50 (m, 5H), 7.72 (br s, 1H), 8.55 (br s, 1H); MS m/z 333 [M+H]⁺.

Step 2(2S,5R)—N′-Acetyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

The compound (2.48 g, 7.46 mmol) of the above Step 1 was dissolved inmethanol (50 mL), followed by adding 10% palladium-carbon (50% watercontent, 313 mg), and stirring under hydrogen atmosphere at roomtemperature for 40 minutes. The catalyst of the reaction mixture wasfiltered through Celite and the solvent was concentrated under reducedpressure to afford 1.88 g of the title compound (quantitative).

[α]_(D) ²⁰−30.5° (c 0.59, MeOH); ¹H NMR (400 MHz, CD₃OD) δ 1.70-1.79 (m,1H), 1.87-2.11 (m, 2H), 2.00 (s, 3H), 2.27 (br dd, J=15.0, 6.6 Hz, 1H),3.15 (br d, J=12.0 Hz, 1H), 3.24 (d, J=12.0 Hz, 1H), 3.67-3.73 (m, 1H),3.95 (d, J=7.2 Hz, 1H); MS m/z 243 [M+H]⁺.

Step 3 Sodium(2S,5R)—N′-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the compound (1.87 g, 7.71 mmol) of the above Step 2 inpyridine (35 mL) was added sulfur trioxide-pyridine complex (5.51 g),followed by agitating at room temperature overnight. To the reactionsolution was added methylene chloride, and filtrated, followed byconcentrating under reduced pressure. To the resulting residue was addedtoluene, followed by azeotropy and concentration to dryness. The mixturewas added to saturated phosphoric acid dihydrogen sodium aqueoussolution (200 mL), followed by washing with ethyl acetate. Subsequently,tetrabutylammonium hydrogen sulfate (3.17 g) and ethyl acetate wereadded, followed by stirring for 10 minutes and then layer separation.The organic layer was dried over anhydrous sodium sulfate, followed byfiltration and concentration under reduced pressure. The resultingresidue was purified by silica gel column chromatography (methylenechloride/acetone/triethylamine=49/49/2) to afford 3.27 g oftetrabutylammonium(2S,5R)—N′-acetyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide.

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.3 Hz, 12H), 1.45 (sex, J=7.3 Hz,8H), 1.60-1.82 (m, 9H), 1.86-1.98 (m, 1H), 2.08 (s, 3H), 2.13-2.24 (m,1H), 2.35 (br dd, J=15.2, 6.8 Hz, 1H), 3.17 (d, J=12.0 Hz, 1H),3.23-3.40 (m, 8H), 3.37 (br d, J=12.0 Hz, 1H), 4.00 (d, J=7.6 Hz, 1H),4.34 (br s, 1H), 7.92 (br s, 1H), 8.62 (br s, 1H); MS m/z 323[M−Bu₄N+2]⁺.

The above tetrabutylammonium salt was reacted with DOWEX (Na type), andthen subjected to octadecyl silica gel column chromatography (water) toafford 1.73 g of the title compound (yield 65%).

[α]_(D) ²¹−44.9° (c 0.55, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.64-1.75 (m,1H), 1.75-1.91 (m, 1H), 1.91-2.02 (m, 1H), 1.95 (s, 3H), 2.05-2.14 (m,1H), 3.09 (d, J=12.6 Hz, 1H), 3.23 (br d, J=12.6 Hz, 1H), 4.05 (br d,J=7.2 Hz, 1H), 4.09 (br dd, J=5.8, 3.0 Hz, 1H); MS m/z 323 [M−Na+2H]⁺;Na content 8.2%.

Example 22 Sodium(2S,5R)-7-oxo-N′-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the carboxylic acid of Example 9 or 16 (6b, 354 mg,1.28 mmol) in tetrahydrofuran (10 mL) were added triethylamine (0.216mL) and isobutyl chloroformate (208 p,1) under ice-cooling, followed byagitating at 0° C. for 15 minutes. To the reaction solution were added asolution of propionohydrazide (161 mg, prepared following a procedureanalogous to Reference Example 3 and Reference Example 6) intetrahydrofuran (3 mL) at 0° C., followed by stirring at roomtemperature for 1 hour, and then concentrating under reduced pressure.The resulting residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1-0/1) to afford 425 mg of the title compound(yield 96%).

[α]_(D) ²¹+95.6° (c 0.46, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.20 (t,J=7.6 Hz, 3H), 1.56-1.66 (m, 1H), 1.91-2.05 (m, 2H), 2.25-2.40 (m, 3H),3.09 (br d, J=12.0 Hz, 1H), 3.17 (d, J=12.0 Hz, 1H), 3.29-3.34 (m, 1H),4.02 (d, J=7.6 Hz, 1H), 4.92 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz,1H), 7.33-7.46 (m, 5H), 7.58 (br d, J=3.0 Hz, 1H), 8.50 (br d, J=3.0 Hz,1H); MS m/z 347 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

The compound (417 mg, 1.20 mmol) of the above Step 1 was dissolved inmethanol (10 mL), 10% palladium-carbon (50% water content, 110 mg) wasadded, followed by stirring under hydrogen atmosphere at roomtemperature for 50 minutes. The catalyst of the reaction mixture wasfiltered through Celite and the solvent was concentrated under reducedpressure to afford 297 mg of the title compound (yield 96%).

¹H NMR (400 MHz, CD₃OD) δ 1.17 (t, J=7.6 Hz, 3H), 1.69-1.79 (m, 1H),1.88-1.99 (m, 1H), 2.02-2.11 (m, 1H), 2.24-2.32 (m, 1H), 2.28 (q, J=7.6Hz, 2H), 3.16 (br d, J=11.6 Hz, 1H), 3.26 (d, J=11.6 Hz, 1H), 3.68-3.72(m, 1H), 3.95 (d, J=7.6 Hz, 1H); MS m/z 257 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-N′-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the compound (296 mg, 1.15 mmol) of the above Step 2 inpyridine (7.5 mL), sulfur trioxide-pyridine complex (843 mg) was added,followed by agitating at room temperature overnight. To the reactionsolution was added methylene chloride, followed by filtering andconcentrating under reduced pressure. To the residue was added toluene,followed by azeotropy. Thereby, pyridinium(2S,5R)-7-oxo-N′-propanoyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, followed by neutralizing with half-saturated sodiumbicarbonate aqueous solution and then purifying octadecyl silica gelcolumn chromatography to afford 357 mg of the title compound (yield86%).

[α]_(D) ²¹−46.7° (c 0.28, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.02 (t, J=7.6Hz, 3H), 1.64-1.76 (m, 1H), 1.78-1.90 (m, 1H), 1.93-2.02 (m, 1H), 2.10(br dd, J=15.6, 7.2 Hz, 1H), 2.22 (q, J=7.6 Hz, 2H), 3.10 (d, J=12.0 Hz,1H), 3.23 (br d, J=12.0 Hz, 1H), 4.04 (d, J=7.2 Hz, 1H), 4.07-4.12 (m,1H); MS m/z 337 [M−Na+2H]⁺.

Example 23 Sodium(2S,5R)—N′-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from the carboxylic acid(6b, 363 mg, 1.31 mmol) of Example 9 or 16 and isobutyrohydrazide (190mg), 440 mg of the title compound was afforded (yield 93%).

[α]_(D) ²⁰+86.6° (c 0.50, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.21 (d,J=6.8 Hz, 3H), 1.23 (d, J=6.8 Hz, 3H), 1.55-1.63 (m, 1H), 1.91-2.07 (m,2H), 2.30-2.38 (m, 1H), 2.48 (sep, J=6.8 Hz, 1H), 3.09 (br d, J=12.0 Hz,1H), 3.18 (d, J=12.0 Hz, 1H), 3.28-3.32 (m, 1H), 4.02 (br d, J=7.6 Hz,1H), 4.92 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz, 1H), 7.34-7.53 (m,6H), 8.47 (br d, J=3.6 Hz, 1H); MS m/z 361 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from the compound (426mg, 1.18 mmol) of the above Step 1, 308 mg of the title compound wasafforded (yield 97%). ¹H NMR (400 MHz, CD₃OD) δ 1.16 (d, J=7.0 Hz, 3H),1.17 (d, J=7.0 Hz, 3H), 1.70-1.79 (m, 1H), 1.87-1.99 (m, 1H), 2.02-2.12(m, 1H), 2.27 (br dd, J=15.0, 7.0 Hz, 1H), 2.53 (sep, J=7.0 Hz, 1H),3.16 (br d, J=12.0 Hz, 1H), 3.27 (d, J=12.0 Hz, 1H), 3.67-3.73 (m, 1H),3.94 (br d, J=7.6 Hz, 1H); MS m/z 271 [M+H]⁺.

Step 3 Sodium(2S,5R)—N′-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 22, from the compound (303mg, 1.12 mmol) of the above Step 2, pyridinium(2S,5R)—N′-(2-methylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, followed by purifying by octadecyl silica gel columnchromatography, and 261 mg of the title compound was afforded (yield62%).

[α]_(D) ²⁰−40.3° (c 0.94, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.01 (d, J=6.8Hz, 6H), 1.62-1.73 (m, 1H), 1.76-1.88 (m, 1H), 1.91-2.00 (m, 1H), 2.08(br dd, J=15.6, 6.8 Hz, 1H), 2.46 (sep, J=6.8 Hz, 1H), 3.09 (d, J=12.4Hz, 1H), 3.21 (br d, J=12.4 Hz, 1H), 4.03 (d, J=7.6 Hz, 1H), 4.06-4.10(m, 1H); MS m/z 351 [M−Na+2H]⁺.

Example 24 Sodium(2S,5R)—N′-(2,2-dimethylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-N′-(2,2-dimethylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 18, from the carboxylic acid(6b, 400 mg, 1.44 mmol) of Example 9 or 16 and pivalic acid hydrazide(185 mg, 1.59 mmol), 506 mg of the title compound was afforded (yield93%).

¹H NMR (400 MHz, CDCl₃) δ 1.14 (s, 9H), 1.49-1.54 (m, 1H), 1.77-1.88 (m,2H), 2.14-2.19 (m, 1H), 2.93 (d, J=2.9, 1H), 3.11 (d, J=2.9, 1H), 3.18(br s, 1H), 3.85 (d, J=1.8, 1H), 4.78 (d, J=2.8, 1H), 4.92 (d, J=2.8,1H), 7.18-7.31 (m, 5H), 8.51 (s, 1H), 5.52 (s, 1H); MS m/z 375 [M+H]⁺.

Step 2(2S,5R)—N′-(2,2-Dimethylpropanoyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

Step 3 Sodium(2S,5R)—N′-(2,2-dimethylpropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 18, from all the amount ofthe compound of the above Step 2, and purification by octadecyl silicagel column chromatography, 404 mg of the title compound was afforded(yield 77%).

¹H NMR (400 MHz, D₂O) δ 1.09 (s, 3H), 1.10 (s, 3H), 1.11 (d, J=0.2, 3H),1.67-1.73 (m, 1H), 1.74-1.88 (m, 1H), 1.95-1.99 (m, 1H), 2.08-2.14 (m,1H), 3.14 (d, J=3.1, 1H), 3.22 (d, J=3.2, 1H), 3.70 (d, J=0.6, 1H), 4.04(d, J=1.9, 1H), 4.10 (d, J=0.7, 1H); MS m/z 365 [M−Na+2H]⁺, 363 [M−Na]⁻.

Example 25 Sodium(2SR,5RS)-N′-acetyl-N′-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2SR,5RS)-N′-Acetyl-6-benzyloxy-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (148 mg, 0.536 mmol) and N-methylacetohydrazide (64.0 mg, preparedfrom methylhydrazine and acetic anhydride), 221 mg of the title compoundwas afforded (yield 88%).

¹H NMR (400 MHz, CDCl₃) δ 1.59-1.73 (m, 1H), 1.88-2.10 (m, 2H), 2.02 (s,1.8H), 2.17 (s, 1.2H), 2.31-2.39 (m, 1H), 2.69 (d, J=11.6 Hz, 0.6H),3.07 (br d, J=11.6 Hz, 0.4H), 3.11-3.38 (m, 2H), 3.13 (s, 1.8H), 3.30(s, 1.2H), 4.01 (d, J=7.2 Hz, 1H), 4.92 (d, J=11.6 Hz, 1H), 5.06 (d,J=11.6 Hz, 0.4H), 5.07 (d, J=11.2 Hz, 0.6H), 7.31-7.53 (m, 5H), 8.49 (brs, 0.4H), 8.58 (br s, 0.6H); MS m/z 347 [M+H]⁺.

Step 2(2SR,5RS)-N′-Acetyl-6-hydroxy-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from the compound (216mg, 0.624 mmol) of the above Step 1, 156 mg of the title compound wasafforded (yield 98%).

¹H NMR (400 MHz, CD₃OD) δ 1.74-1.83 (m, 1H), 1.89-2.04 (m, 1H), 2.01 (s,2.5H), 2.06-2.14 (m, 1H), 2.17 (s, 0.5H), 2.22-2.32 (m, 1H), 2.96 (d,J=11.6 Hz, 0.8H), 3.06-3.24 (m, 1.2H), 3.11 (s, 2.5H), 3.28 (s, 0.5H),3.68-3.74 (m, 1H), 3.96 (br d, J=7.6 Hz, 1H); MS m/z 257 [M+H]⁺.

Step 3 Sodium(2SR,5RS)-N′-acetyl-N′-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 22, the compound (150 mg,0.585 mmol) of the above Step 2, pyridinium(2SR,5RS)-N′-acetyl-N′-methyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by DIAION HP21 (MITSUBISHI CHEMICAL) columnchromatography, 148 mg of the title compound was afforded (yield 71%).

¹H NMR (400 MHz, D₂O) δ 1.67-1.80 (m, 1H), 1.80-2.04 (m, 2H), 1.93 (s,2.4H), 2.05-2.16 (m, 1H), 2.09 (s, 0.6H), 2.98 (d, J=12.0 Hz, 0.8H),3.00 (s, 2.4H), 3.11 (d, J=12.0 Hz, 0.2H), 3.18 (s, 0.6H), 3.20 (br d,J=12.0 Hz, 0.2H), 3.28 (br d, J=12.0 Hz, 0.8H), 4.01-4.15 (m, 2H); MSm/z 337 [M−Na+2H]⁺.

Example 26(2SR,5RS)-N′-(Aminoacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl[2-(2-{[(2SR,5RS)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamate

To a solution of(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (153 mg, 0.554 mmol) in tetrahydrofuran (3 mL) were addedtriethylamine (0.232 mL) and isobutyl chloroformate (89.1 μl) underice-cooling, followed by agitating at 0° C. for 45 minutes. To thereaction solution was added a solution of tert-butyl2-hydrazinyl-2-oxoethylcarbamate (129 mg, prepared following a procedureanalogous to Reference Example 5 and Reference Example 6) intetrahydrofuran (3 mL) at 0° C., followed by stirring at roomtemperature for 2.5 hours and concentrating under reduced pressure. Theresulting residue was purified by silica gel column chromatography(hexane/ethyl acetate=7/3-0/10) to afford 179 mg of the title compound(yield 72%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.57-1.70 (m, 1H), 1.91-2.06 (m,2H), 2.28-2.38 (m, 1H), 3.07 (br d, J=12.0 Hz, 1H), 3.12 (d, J=12.0 Hz,1H), 3.29-3.34 (m, 1H), 3.88 (dd, J=16.3, 6.1 Hz, 1H), 3.92 (dd, J=16.3,6.1 Hz, 1H), 4.02 (br d, J=7.2 Hz, 1H), 4.91 (d, J=11.2 Hz, 1H), 5.05(d, J=11.2 Hz, 1H), 5.24 (br t, J=6.1 Hz, 1H), 7.34-7.46 (m, 5H), 8.42(br s, 1H), 8.53 (br s, 1H); MS m/z 448 [M+H]⁺.

Step 2 tert-Butyl[2-(2-{[(2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamate

The compound (176 mg, 0.394 mmol) of the above Step 1 was dissolved inmethanol (4 mL), followed by adding 10% palladium-carbon (50% watercontent, 42.4 mg), and stirring under hydrogen atmosphere at roomtemperature for 40 minutes. The catalyst of the reaction mixture wasfiltered through Celite, the solvent was concentrated under reducedpressure to afford 140 mg of the title compound (quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.45 (s, 9H), 1.69-1.79 (m, 1H), 1.87-2.00 (m,1H), 2.01-2.11 (m, 1H), 2.27 (br dd, J=15.0, 6.6 Hz, 1H), 3.16 (br d,J=12.0 Hz, 1H), 3.24 (d, J=12.0 Hz, 1H), 3.67-3.73 (m, 1H), 3.81 (s,2H), 3.95 (br d, J=7.2 Hz, 1H); MS m/z 358 [M+H]⁺.

Step 3(2SR,5RS)-N′-(Aminoacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of the compound (137 mg, 0.382 mmol) of the above Step 2in pyridine (4 mL) was added sulfur trioxide-pyridine complex (276 mg),followed by agitating at room temperature overnight. To the reactionsolution was added methylene chloride, followed by filtration andconcentration under reduced pressure. To the resulting residue was addedtoluene, followed by azeotropy. Thereby 405 mg of pyridinium tert-butyl[2-(2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]carbamatewas afforded. MS m/z 438 [M−C₅H₅N+H]⁺.

All the amount of the pyridinium salt was dissolved in methylenechloride (5 mL), and trifluoroacetic acid (1.7 mL) was added, followedby agitating at room temperature for 3.5 hours. The reaction solutionwas concentrated under reduced pressure. The resulting residue waswashed with diethyl ether, and adjusted to pH 7 with sodium bicarbonateaqueous solution and lyophilized. The resulting crude product waspurified by SEPABEADS SP207 (MITSUBISHI CHEMICAL)(acetonitrile/water=0/100-10/90). After lyophilisation, 42.6 mg of thetitle compound was afforded (2 steps, yield 33%).

¹H NMR (400 MHz, D₂O) δ 1.63-1.74 (m, 1H), 1.78-1.89 (m, 1H), 1.92-2.02(m, 1H), 2.05-2.14 (m, 1H), 3.08 (d, J=12.4 Hz, 1H), 3.23 (br d, J=12.4Hz, 1H), 4.06 (br d, J=6.4 Hz, 1H), 4.07-4.12 (m, 1H); MS m/z 338[M+H]⁺.

Example 27(2S,5R)—N′-(3-Aminopropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl[3-(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate

To a solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example9 or 16 in methylene chloride (14.1 mL) were added triethylamine (393μl), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (406mg), 1-hydroxybenzotriazole monohydrate (324.6 mg), and tert-butyl(3-hydrazinyl-3-oxopropyl)carbamate (430.8 mg, prepared following aprocedure analogous to Reference Example 2), followed by agitating atroom temperature overnight. The reaction solution was concentrated underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate) to afford 347.3 mg of the titlecompound (yield 53.3%).

¹H NMR (400 MHz, CD₃OD) δ 1.32 (s, 9H), 1.55-1.63 (m, 1H), 1.75-1.91 (m,2H), 2.11-2.17 (m, 1H), 2.31-2.34 (t, J=6.4 Hz, 2H), 2.92-2.95 (br d,J=11.6 Hz, 1H), 3.09-3.12 (d, J=11.6 Hz, 1H), 3.20-3.26 (t, J=6.4 Hz,2H), 3.47 (br s, 1H), 3.86-3.88 (d, J=7.6 Hz, 1H), 4.82-4.85 (d, J=11.2Hz, 1H), 4.89-4.92 (d, J=11.2 Hz, 1H), 7.27-7.31 (m, 3H), 7.35-7.38 (m,2H); MS m/z 462 [M+H]⁺.

Step 2 tert-Butyl[3-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate

All amount of the compound of the above Step 1 was dissolved in methanol(7.5 mL), followed by adding 10% palladium-carbon (50% water content, 69mg) and stirring under hydrogen atmosphere at room temperature for 1hour. The catalyst of the reaction mixture was filtered through Celiteand the solvent was concentrated under reduced pressure to afford thetitle compound (quantitative).

Step 3(2S,5R)—N′-(3-Aminopropanoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of all the amount of the compound of the above Step 2 inpyridine (7.5 mL) was added sulfur trioxide-pyridine complex (598.4 mg),followed by agitating at room temperature overnight. To the reactionsolution was added methylene chloride, followed by filtration andconcentration under reduced pressure. To the resulting residue was addedtoluene, followed by azeotropy. Thereby pyridinium tert-butyl[3-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-3-oxopropyl]carbamate(quantitative) was afforded. MS m/z 450 [M—C₅H₅N—H]⁻.

All the amount of the above pyridine salt was deprotected withtrifluoroacetic acid, and purified by octadecyl silica gel columnchromatography to afford 191 mg of the title compound (yield 72.3%).

¹H NMR (400 MHz, D₂O) δ 1.62-1.70 (m, 1H), 1.76-1.86 (m, 1H), 1.92-1.95(m, 1H), 2.04-2.09 (m, 1H), 2.60-2.63 (t, J=6.8 Hz, 2H),3.04-3.07 (d,J=12.0 Hz, 1H), 3.13-3.16 (t, J=6.8 Hz, 2H), 3.18-3.22 (d, J=11.6 Hz,1H), 4.02-4.03 (d, J=7.2 Hz, 1H), 4.06 (br s, 1H); MS m/z 352 [M+H]⁺.

Example 28(2S,5R)—N′-[(4-Aminophenyl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl{4-[2-(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(4-(2-hydrazinyl-2-oxoethyl)phenyl)carbamate (682.6 mg, preparedfollowing a procedure analogous to Reference Example 5 and ReferenceExample 6), 550.8 mg of the title compound was afforded (yield 74.6%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.56-1.64 (m, 1H), 1.86-1.97 (m,2H), 2.27-2.33 (m, 1H), 3.03-3.06 (br d, J=11.6 Hz, 1H), 3.12-3.15 (d,J=11.6 Hz, 1H),3.27 (br s, 1H), 3.75 (s, 2H), 3.96-3.98 (d, J=6.8 Hz,1H), 4.87-4.89 (d, J=11.2 Hz, 1H), 5.01-5.04 (d, J=11.6 Hz, 1H), 6.47(s, 1H), 7.21-7.24 (br d, J=10.8 Hz, 2H), 7.32-7.49 (m, 7H), 8.47 (br s,1H); MS m/z 524 [M+H]⁺.

Step 2 tert-Butyl{4-[2-(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 425 mg of the title compound wasafforded (yield 93.2%). MS m/z 434 [M+H]⁺.

Step 3(2S,5R)—N′-[(4-Aminophenyl)acetyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{4-[2-(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)-2-oxoethyl]phenyl}carbamatewas afforded (quantitative). MS m/z 512 [M−Bu₄N]⁻.

All the amount of the tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and purified by octadecyl silica gel columnchromatography to afford 226 mg of the title compound (yield 55.8%).

¹H NMR (400 MHz, D₂O) δ 1.61-1.69 (m, 1H), 1.74-1.84 (m, 1H), 1.90-1.94(m, 1H), 2.03-2.08 (m, 1H), 3.03-3.06 (d, J=12.0 Hz, 1H), 3.16-3.19 (d,J=12.0 Hz, 1H), 3.43 (br s, 2H), 3.99-4.01 (d, J=7.6 Hz, 1H), 4.05 (brs, 1H), 6.67-6.69 (d, J=8.4 Hz, 1H), 7.00-7.02 (d, J=8.4 Hz, 1H); MS m/z412 [M−H]⁻.

Example 29 Sodium(2S,5R)—N′-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-N′-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and 2-methoxyacetohydrazide(220.7 mg), 397.1 mg of the title compound was afforded (yield 77.7%).

¹H NMR (400 MHz, CDCl₃) δ 1.50-1.59 (m, 1H), 1.85-1.94 (m, 2H),2.26-2.33 (m, 1H), 3.01-3.04 (br d, J=12.4 Hz, 1H), 3.06-3.09 (d, J=12.0Hz, 1H), 3.24 (s, 1H), 3.39 (s, 3H), 3.97-4.00 (m, 3H), 4.83-4.86 (d,J=11.6 Hz, 1H), 4.97-5.00 (d, J=11.6 Hz, 1H), 7.27-7.37 (m, 5H), 8.22(m, 1H), 8.44 (m,1H); MS m/z 363 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N′-(methoxyacetyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 273 [M+H]⁺.

Step 3 Sodium(2S,5R)—N′-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N′-(methoxyacetyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution. After purification by SEPABEADS SP207 (MITSUBISHI CHEMICAL)column chromatography, 134.4 mg of the title compound was afforded(yield 32.7%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.73 (m, 1H), 1.77-1.87 (m, 1H), 1.93-1.96(m, 1H), 2.05-2.11 (m, 1H), 3.06-3.09 (br d, J=12.0 Hz, 1H), 3.19-3.22(d, J=12.8 Hz, 1H), 3.31 (s, 3H), 3.97-4.04 (m, 3H), 4.07 (s, 1H); MSm/z 353 [M−Na+2H]⁺.

Example 30 Sodium(2SR,5RS)-N′-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2SR,5RS)-N′-Benzoyl-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (100.0 mg, 0.36 mmol) and benzohydrazide (54.2 mg) intetrahydrofuran (4 mL) were added triethylamine (231 μL) and2-chloro-1-methylpyridine-1-ium iodide (138.7 mg), followed by stirringat room temperature overnight. To the reaction solution was addedsaturated sodium bicarbonate aqueous solution, followed by extractingwith chloroform. The organic layer was dried over sodium sulfate andthen concentrated. The resulting crude product was purified by silicagel column chromatography to afford 123.0 mg of the title compound(yield 86%).

MS m/z 395 [M+H]⁺.

Step 2(2SR,5RS)-N′-Benzoyl-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of all the amount of the compound of the above Step 1 inmethanol (3 mL) was added 50% palladium-carbon (50% water content, 20mg), followed by stirring under hydrogen atmosphere at room temperaturefor 1 h. The catalyst in the reaction mixture was filtered off throughPTFE membrane, followed by concentrating under reduced pressure. Theresulting crude product was purified by silica gel column chromatographyto afford 30 mg of the title compound (yield 32%)

¹H NMR (400 MHz, CD₃OD) δ 1.76-1.80 (m, 1H), 1.94-2.00 (m, 1H),2.29-2.31 (m, 1H), 3.20-3.38 (m, 1H), 3.73 (br s, 1H), 4.02 (d, J=1.9,1H), 7.47-7.90 (m, 1H); m/z 305 [M+H]⁺.

Step 3 Sodium(2SR,5RS)-N′-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of all the amount of the compound of the above Step 2 inmethylene chloride (2.0 mL) were added 2,6-lutidine (145 μL) and sulfurtrioxide-pyridine complex (63 mg), followed by agitating at roomtemperature overnight. To the reaction solution was added chloroform,followed by liquid separation with water. The aqueous layer wasconcentrated to 1 mL under reduced pressure, followed by purification byoctadecyl silica gel column chromatography. The resulting pyridinium(2SR,5RS)-N′-benzoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas salt-exchanged with Dowex-Na type to afford 4 mg of the titlecompound (yield 37%).

¹H NMR (400 MHz, D₂O) δ 1.73-1.75 (m, 1H), 1.82-1.95 (m, 1H), 2.10-2.15(m, 1H), 3.16 (d, J=3.2, 1H), 3.26 (d, J=3.0, 1H), 4.09 (m, 2H),7.39-7.54 (m, 5H); MS m/z 385 [M−Na+2H]⁺.

Example 31(2S,5R)—N′-(4-Aminobenzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl{4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(4-(hydrazinecarbonyl)phenyl)carbamate (653 mg, prepared followingprocedures analogous to Reference Example 5 and Reference Example 6),689.5 mg of the title compound was afforded (yield 96.0%).

¹H NMR (400 MHz, CD₃OD) δ 1.52 (s, 9H), 1.68-1.75 (m, 1H), 1.89-2.00 (m,2H), 2.24-2.30 (m, 1H), 3.07-3.10 (d, J=10.8 Hz, 1H), 3.30 (m, 1H), 3.58(br s,1H), 4.02-4.04 (d, J=7.6 Hz, 1H), 4.93-4.59 (d, J=11.6 Hz, 1H),5.00-5.03 (d, J=11.6 Hz, 1H), 7.33-7.41 (m, 3H), 7.46-7.48 (m, 2H), 7.51(d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H); MS m/z 510 [M+H]⁺.

Step 2 tert-Butyl{4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 420 [M+H]⁺

Step 3(2S,5R)—N′-(4-Aminobenzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]phenyl}carbamatewas afforded (quantitative). MS m/z 498 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid and purified by octadecyl silica gel columnchromatography to afford 127.4 mg of the title compound (yield 23.6%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.73 (m, 1H), 1.78-1.88 (m, 1H), 1.93-1.97(m, 1H), 2.08-2.13 (m, 1H), 3.14-3.17 (d, J=12.0 Hz, 1H), 3.26-3.26 (d,J=12.0 Hz, 1H), 4.07 (m, 2H), 6.69-6.71 (d, J=8.4 Hz, 2H), 7.52-7.54 (d,J=8.4 Hz, 2H); MS m/z 400 [M+H]⁺.

Example 32(2SR,5RS)-N′-(4-(Aminomethyl)benzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl{4-[(2-{[(2SR,5RS)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate

Following a procedure analogous to Example 27, from(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (200 mg, 0.724 mmol) and tert-butyl4-(hydrazinecarbonyl)benzylcarbamate (226 mg, prepared followingprocedures analogous to Reference Example 5 and Reference Example 6),288.7 mg of the title compound was afforded (yield 76.1%).

¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 1.62 (m, 1H), 1.95-2.05 (m, 2H),2.34-2.39 (m, 1H), 3.14 (br d, J=11.6 Hz, 1H), 3.20 (d, J=11.6 Hz, 1H),3.34 (s, 1H), 4.07 (d, J=6.8 Hz, 1H), 4.36 (br d, J=5.6 Hz, 2H), 4.92(d, J=11.6 Hz, 1H), 5.06 (d, J=11.4 Hz, 1H), 7.34-7.52 (m, 7H), 7.83 (d,J=8.4 Hz, 2H); MS m/z 524 [M+H]⁺.

Step 2 tert-Butyl{4-[(2-{[(2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 216.1 mg of the title compound wasafforded (yield 90.4%).

¹H NMR (400 MHz, CD₃OD) δ 1.45 (s, 9H), 1.74-1.82 (m, 1H), 1.91-2.03 (m,1H), 2.09-2.20 (m, 1H), 2.29-2.34 (m, 1H), 3.20-3.30 (m, 2H), 3.74 (s,1H), 4.02 (d, J=7.6 Hz, 1H), 4.29 (br s, 2H), 7.39 (d, J=8.0 Hz, 2H),7.86 (d, J=8.0 Hz, 2H);

Step 3(2SR,5RS)-N′-(4-(Aminomethyl)benzoyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 26, from all the amount ofthe compound of the above Step 2, pyridinium tert-butyl{4-[(2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]benzyl}carbamatewas afforded (quantitative).

¹H NMR (400 MHz, D₂O) δ 1.29 (s, 9H), 1.74-1.76 (m, 1H), 1.81-1.89 (m,1H), 1.96-1.91 (m, 1H), 2.11-2.15 (m, 1H), 3.18 (d, J=12.8 Hz, 1H), 3.27(d, J=12.8 Hz, 1H), 3.59 (s, 1H), 4.12 (d, J=4.4 Hz, 1H), 4.19 (br s,2H), 7.32 (d, J=7.6 Hz, 2H), 7.68 (d, J=7.6 Hz, 2H), 7.91-8.63 (m, 5H):

All the amount of the pyridine salt was deprotected with trifluoroaceticacid, and purified by DIAION HP21 (MITSUBISHI CHEMICAL) to afford 100.3mg of the title compound (yield 48.7%).

¹H NMR (400 MHz, D₂O) δ 1.80-1.88 (m, 1H), 1.94-2.00 (m, 1H), 2.08 (m,1H), 2.24-2.28 (m, 1H), 3.30 (d, J=12.4 Hz, 1H), 3.40 (d, J=12.0 Hz,1H), 4.20-4.24 (m, 4H), 7.62 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.0 Hz, 2H);MS m/z 414 [M+H]⁺.

Example 33 Sodium(2SR,5RS)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2SR,5RS)-6-Benzyloxy-7-oxo-N-(2-oxopyrrolidin-1-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (164 mg, 0.594 mmol) and 1-aminopyrrolidin-2-one hydrochloride (101mg), 128 mg of the title compound was afforded (yield 60%).

¹H NMR (400 MHz, CDCl₃) δ 1.57-1.70 (m, 1H), 1.88-2.22 (m, 4H),2.30-2.52 (m, 3H), 3.09 (br d, J=12.0 Hz, 1H), 3.22 (d, J=12.0 Hz, 1H),3.30-3.35 (m, 1H), 3.46 (ddd, J=8.5, 8.5, 4.8 Hz, 1H), 3.73 (q, J=7.7Hz, 1H), 4.02 (br d, J=7.6 Hz, 1H), 4.92 (d, J=11.2 Hz, 1H), 5.06 (d,J=11.2 Hz, 1H), 7.35-7.46 (m, 5H), 8.34 (br s, 1H); MS m/z 359 [M+H]⁺.

Step 2(2SR,5RS)-6-Hydroxy-7-oxo-N-(2-oxopyrrolidin-1-yl)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from the compound (126mg, 0.352 mmol) of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.70-1.80 (m, 1H), 1.88-2.00 (m, 1H),2.02-2.19 (m, 3H), 2.27 (br dd, J=15.0, 7.0 Hz, 1H), 2.40-2.47 (m, 2H),3.16 (br d, J=11.6 Hz, 1H), 3.21 (d, J=11.6 Hz, 1H), 3.52-3.65 (m, 2H),3.68-3.73 (m, 1H), 3.96 (d, J=7.6 Hz, 1H); MS m/z 269 [M+H]⁺.

Step 3 Sodium(2SR,5RS)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of all the amount of the compound of the above Step 2 inpyridine (3.5 mL) was added sulfur trioxide-pyridine complex (248 mg),followed by agitating at room temperature overnight. To the reactionsolution was added methylene chloride, followed by filtration andconcentration under reduced pressure. To the resulting residue was addedtoluene, followed by azeotropy. Thereby, 178 mg of pyridinium(2SR,5RS)-7-oxo-N-(2-oxopyrrolidin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded. MS m/z 349 [M−C₅H₅NH]⁺.

All the amount of the above pyridinium salt was added to water andsaturated sodium bicarbonate aqueous solution and adjusted to pH 7,followed by lyophilisation. The resulting crude product was purified byDIAION HP21 (MITSUBISHI CHEMICAL) (acetonitrile/water=100/0-90/10),followed by lyophilisation, and 103 mg of the title compound wasafforded (2 steps, yield79%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.74 (m, 1H), 1.77-1.89 (m, 1H), 1.92-2.14(m, 2H), 2.03 (qui, J=7.6 Hz, 2H), 2.38 (t, J=7.6 Hz, 2H), 3.06 (d,J=12.0 Hz, 1H), 3.23 (br d, J=12.0 Hz, 1H), 3.49 (t, J=7.6 Hz, 2H), 4.05(br d, J=6.8 Hz, 1H), 4.08 (br dd, J=5.8, 3.0 Hz, 1H); MS m/z 349[M−Na+2H]⁺.

Example 34 Sodium(2S,5R)-7-oxo-6-(sulfooxy)-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-7-oxo-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 andtetrahydro-2H-pyran-4-carbohydrazide (952 mg) described in ReferenceExample 2, 309.8 mg of the title compound was afforded (yield 54.5%).

¹H NMR (400 MHz, CD₃OD) δ 1.69-2.00 (m, 7H), 2.20-2.25 (m, 1H),2.49-2.57 (m, 1H), 3.02 (br d, J=12.0 Hz, 1H), 3.20 (d, J=12.0 Hz, 1H),3.41-3.47 (m, 2H), 3.56 (s, 1H), 3.94-3.97 (m, 3H), 4.91-4.94 (d, J=11.2Hz, 1H), 4.98-5.01 (d, J=11.2 Hz, 1H), 7.34-7.47 (m, 5H); MS m/z 403[M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-7-oxo-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 313 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-6-(sulfooxy)-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)-7-oxo-6-(sulfooxy)-N′-(tetrahydro-2H-pyran-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by SEPABEADS SP207 (MITSUBISHI CHEMICAL)column chromatography to afford 198.9 mg of the title compound (yield62.4%).

¹H NMR (400 MHz, D₂O) δ 1.57-1.66 (m, 5H), 1.76-1.86 (m, 1H), 1.93 (m,1H), 2.05-2.09 (m, 1H), 2.52-2.56 (m, 1H), 3.07-3.10 (br d, J=12.0 Hz,1H), 3.20-3.23 (d, J=12.0 Hz, 1H), 3.36-3.41 (m, 2H), 3.86-3.89 (d,J=10.0 Hz, 2H), 4.02-4.04 (J=7.6 Hz, 1H), 4.07(s, 1H); MS m/z 393[M−Na+2H]⁺.

Example 35(2S,5R)-7-Oxo-N′-(piperidine-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl4-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl4-(hydrazinecarbonyl)piperidine-1-carboxylate (642 mg, preparedfollowing a procedure analogous to Reference Example 5 and ReferenceExample 6), 552.7 mg of the title compound was afforded (yield 78.1%).

¹H NMR (400 MHz, CDCl₃) δ 1.42 (s, 9H), 1.60-1.71 (m, 3H), 1.77-1.92 (m,2H), 1.96-2.02 (m, 2H),2.28-2.36 (m, 2H),2.72-2.78 (dd, J=12 Hz, 2H),3.06-3.09 (br d, J=12.0 Hz, 1H), 3.14-3.17 (d, J=11.6 Hz, 1H), 3.28 (brs, 1H), 4.00-4.01 (d, J=7.2 Hz, 1H), 4.07-4.12 (dd, J=14.4 Hz, 2H),4.87-4.90 (d, 11.2 Hz, 1H), 5.02-5.04 (d, J=11.6 Hz, 1H), 7.23-7.41 (m,5H), 7.57 (br s, 1H), 8.58 (br s, 1H); MS m/z 502 [M+H]⁺.

Step 2 tert-Butyl4-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 423.8 mg of the title compound wasafforded (yield 93.6%). MS m/z 412 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N′-(piperidine-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 26, from all the amount ofthe compound of the above Step 2, pyridinium tert-butyl4-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylatewas afforded (quantitative). MS m/z 492 [M−C₅H₅NH]⁺.

All the amount of the pyridine salt was deprotected with trifluoroaceticacid and purified by octadecyl silica gel column chromatography toafford 150 mg of the title compound (yield 37.2%).

¹H NMR (400 MHz, D₂O) δ 1.62-2.10 (m, 8H), 2.57-2.63 (m, 1H), 2.91-2.96(dd, J=11.6, 12.8 Hz, 2H), 3.05-3.08 (d, J=12.4 Hz, 1H), 3.19-3.22 (d,J=12.0 Hz, 1H), 3.33-3.36 (d, J=13.2 Hz, 2H), 4.01-4.03 (d, J=7.6 Hz,1H), 4.07 (br s, 1H); MS m/z 392 [M+H]⁺.

Example 36(2S,5R)-7-Oxo-N′-[(2S)-piperidine-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl(2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-tert-butyl2-(hydrazinecarbonyl)piperidine-1-carboxylate (634 mg, preparedfollowing a procedure analogous to Reference Example 5 and ReferenceExample 6), 567 mg of the title compound was afforded (yield 80%). ¹HNMR (400 MHz, CDCl₃) δ 1.35-1.72 (m, 6H), 1.49 (s, 9H), 1.90-2.10 (m,2H), 2.16-2.40 (m, 2H), 2.98-3.37 (m, 5H), 3.96-4.08 (m, 2H), 4.85 (brs, 1H), 4.92 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.33-7.47 (m,5H), 8.30 (br s, 1H); MS m/z 502 [M+H]⁺.

Step 2 tert-Butyl (2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 410 [M−H]⁻.

Step 3(2S,5R)-7-Oxo-N′-[(2S)-piperidine-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of all the amount of the compound of the above Step 2 inpyridine (11.3 mL) was added sulfur trioxide-pyridine complex (899 mg),followed by agitating at room temperature overnight. To the reactionsolution was added pyridine, followed by filtration and thenconcentration under reduced pressure. To the resulting residue was addedtoluene, followed by azeotropy and concentration to dryness. A saturatedsodium dihydrogen phosphate aqueous solution (15 mL) was added, theaqueous layer was washed with ethyl acetate, and subsequentlytetrabutylammonium hydrogen sulfate (421 mg) and ethyl acetate (30 mL)were added, followed by agitating 10 minutes. The aqueous layer wasextracted with ethyl acetate, then the resulting organic layer was driedover anhydrous sodium sulfate, filtrated, and concentrated under reducedpressure to afford tetrabutylammonium tert-butyl(2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate(quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 12H), 1.30-1.75 (m, 23H),1.44 (s, 9H), 1.84-1.98 (m, 2H), 2.13-2.42 (m, 2H), 2.97-3.12 (m, 1H),3.20-3.46 (m, 10H), 3.80-4.15 (m, 2H), 4.36 (br s, 1H), 4.86 (br s, 1H),8.43 (br s, 1H); MS m/z 490 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was dissolved inmethylene chloride (5.7 mL), and trifluoroacetic acid (5.7 mL) was addedunder ice-cooling, followed by agitating at 0° C. for 30 minutes. Thereaction solution was concentrated under reduced pressure and theresulting residue was washed with diethyl ether, followed by adjustingto pH 7 with sodium bicarbonate aqueous solution, purifying by octadecylsilica gel column chromatography (water), and lyophilizing Thereby, 104mg of the title compound was afforded (3 steps, yield 23%).

¹H NMR (400 MHz, D₂O) δ 1.42-2.17 (m, 10H), 2.83-2.97 (m, 1H), 3.06 (d,J=12.0 Hz, 1H), 3.23 (br d, J=12.0 Hz, 1H), 3.34 (br d, J=12.0 Hz, 1H),3.81 (dd, J=12.0, 3.0 Hz, 1H), 3.99-4.13 (m, 2H); MS m/z 392 [M+H]⁺.

Example 37(2S,5R)-7-Oxo-N′-[(2R)-piperidine-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-butyl(2R)-2-[(2-{[(2S,5R)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl2-(hydrazinecarbonyl)piperidine-1-carboxylate (630 mg, preparedfollowing a procedure analogous to Reference Example; Hydrogenaddition), 648 mg of the title compound was afforded (yield 92%).

¹H NMR (400 MHz, CDCl₃) δ 1.35-1.72 (m, 6H), 1.49 (s, 9H), 1.90-2.06 (m,2H), 2.15-2.40 (m, 2H), 2.80-3.32 (m, 5H), 3.94-4.07 (m, 2H), 4.86 (brs, 1H), 4.92 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz, 1H), 7.34-7.45 (m,5H), 8.40 (br s, 1H); MS m/z 502 [M+H]⁺.

Step 2 tert-Butyl(2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.35-1.60 (m, 2H), 1.46 (s, 9H), 1.60-1.82 (m,4H), 1.87-2.15 (m, 2H), 2.17-2.34 (m, 2H), 3.10-3.20 (m, 2H), 3.24-3.36(m, 2H), 3.67-3.73 (m, 1H), 3.91-4.05 (m, 2H); MS m/z 412 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N′-[(2R)-piperidine-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylatewas afforded (quantitative).

MS m/z 490 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and purified by octadecyl silica gel columnchromatography to afford 158.8 mg of the title compound (3 steps, yield31%).

¹H NMR (400 MHz, D₂O) δ 1.42-1.88 (m, 7H), 1.91-2.01 (m, 1H), 2.03-2.17(m, 2H), 2.88-2.98 (m, 1H), 3.05 (d, J=12.0 Hz, 1H), 3.22 (br d, J=12.0Hz, 1H), 3.35 (br d, J=12.8 Hz, 1H), 3.89 (dd, J=12.0, 3.2 Hz, 1H),3.99-4.13 (m, 2H); MS m/z 392 [M+H]⁺.

Example 38(2S,5R)-7-Oxo-N′-[(2S)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl(2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-tert-butyl2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (573 mg) described inReference Example 6, 555 mg of the title compound was afforded (yield80.1%).

¹H NMR (400 MHz, CD₃OD) δ 1.41 (s, 9H), 1.70-1.73 (m, 1H), 1.86-2.09 (m,5H), 2.13-2.28 (m, 2H), 3.01-3.04 (br d, J=11.6 Hz, 1H), 3.15-3.21 (t,J=11.6 Hz, 1H), 3.31-3.40 (m, 1H), 3.48-3.56 (m, 2H), 3.94-3.96 (d,J=7.2 Hz, 1H), 4.23-4.26 (d, J=7.2 Hz, 1H), 4.91-4.94 (d, J=11.6 Hz,1H), 4.98-5.01 (d, J=11.6 Hz, 1H), 7.34-7.40 (m, 3H), 7.45-7.47 (m, 2H);MS m/z 488 [M+H]⁺.

Step 2 tert-Butyl(2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.41 (s, 9H), 1.70-1.75 (m, 1H), 1.82-2.04 (m,5H), 2.18-2.27 (m, 2H), 3.09-3.21 (m, 2H), 3.32-3.37 (m, 1H), 3.46-3.51(m, 1H), 3.65 (br s, 1H), 3.89-3.91 (d, J 7.6 Hz, 1H), 4.20-4.23 (m,1H); MS m/z 398 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N′-[(2S)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, 782.1 mg of tetrabutylammoniumtert-butyl(2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylatewas afforded (yield 96.3%).

MS m/z 476 [M−Bu₄N]⁻.

All the amount of the tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and purified by octadecyl silica gel columnchromatography to afford 143.8 mg of the title compound (yield 35.2%).

¹H NMR (400 MHz, D₂O) δ 1.66-1.85 (m, 6H), 2.04-2.16 (m, 2H), 2.99-3.30(m, 4H), 3.87-4.18 (m, 3H); MS m/z 378 [M+H]⁺.

Example 39(2S,5R)-7-Oxo-N′-[(2R)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-butyl(2R)-2-[(2-{[(2S,5R)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (573 mg, preparedfollowing procedures analogous to Reference Example 5 and ReferenceExample 6), 624.3 mg of the title compound was afforded (yield 90.8%).

¹H NMR (400 MHz, CDCl₃) δ 1.40 (s, 9H), 1.52-1.57 (m, 1H), 1.81-1.97 (m,5H), 2.25-2.56 (m, 2H), 3.01-3.07 (m, 2H), 3.17 (br s, 1H), 3.17-3.42(m, 2H), 3.94-3.96 (d, J=7.2 Hz, 1H), 4.30 (m, 1H), 4.82-4.85 (d, J=11.2Hz, 1H), 4.97-5.00 (d, J=11.2 Hz, 1H), 7.27-7.37 (m, 5H), 8.37 (br s,1H), 8.94 (br s, 1H); MS m/z 488 [M+H]⁺.

Step 2 tert-Butyl(2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.40 (s, 9H), 1.52-1.57 (m, 1H), 1.81-1.97 (m,5H), 2.25-2.56 (m, 2H), 3.01-3.07 (m, 2H), 3.17 (br s, 1H), 3.17-3.42(m, 2H), 3.94-3.96 (d, J=7.2 Hz, 1H), 4.30 (m, 1H), 4.82-4.85 (d, J=11.2Hz, 1H), 4.97-5.00 (d, J=11.2 Hz, 1H), 7.27-7.37 (m, 5H), 8.37 (br s,1H), 8.94 (br s, 1H); MS m/z 398 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N′-[(2R)-pyrrolidin-2-ylcarbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]pyrrolidine-1-carboxylate(quantitative) was afforded. Subsequently, all the amount of thetetrabutylammonium salt was deprotected with trifluoroacetic acid, andpurified by octadecyl silica gel column chromatography to afford 132.5mg of the title compound (yield 27.4%).

¹H NMR (400 MHz, D₂O) δ 1.68-1.71 (m, 1H), 1.76-1.88 (m, 4H), 1.92 (m,1H), 2.04-2.18 (m, 2H), 2.99-3.02 (d, J=12.0 Hz, 1H), 3.04-3.21 (m, 3H),3.92-4.00 (m, 2H), 4.06 (br s, 1H); MS m/z 378 [M+H]⁺.

Example 40(2S,5R)—N′-{[(2S,4R)-4-Cyclopropylmethylpiperidine-2-yl]carbonyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl(2S,4R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-4-cyclopropylmethylpiperidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (2S,4R)-tert-butyl4-(cyclopropylmethyl)-2-(hydrazinecarbonyl)piperidine-1-carboxylate (595mg, prepared following procedures analogous to Reference Example 5 andReference Example 6), 707.6 mg of the title compound was afforded (yield90.3%).

¹H NMR (400 MHz, CDCl₃) δ 0.01 (m, 2H), 0.40-0.42 (m, 2H), 0.66 (m, 1H),1.18-1.68 (m, 8H), 1.46 (s, 9H), 1.82-2.17 (m, 2H), 2.30-2.34 (m, 1H),3.10-3.18 (m, 2H), 3.29-3.33 (m, 2H), 3.65 (m, 1H), 4.01-4.02 (d, J=7.2Hz, 1H), 4.40-4.44 (m, 1H), 4.89-4.92 (d, J=11.6 Hz, 1H), 5.04-5.07 (d,J=11.2 Hz, 1H), 7.26-7.44 (m, 5H), 8.02 (br s, 1H), 8.39 (br s, 1H); MSm/z 556 [M+H]⁺.

Step 2 tert-Butyl(2S,4R)-4-cyclopropylmethyl-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 0.01 (m, 2H), 0.38 (m, 2H), 0.67 (m, 1H),1.21-1.24 (m, 2H), 1.42 (s, 9H), 1.70-1.94 (m, 6H), 2.06-2.10 (m, 2H),2.19-2.25 (m, 1H), 3.10-3.26 (m, 4H), 3.66 (m, 1H), 3.90-3.92 (d, J=7.2Hz, 1H), 4.25 (m, 1H); MS m/z 466 [M+H]⁺.

Step 3(2S,5R)—N′-{[(2S,4R)-4-Cyclopropylmethylpiperidine-2-yl]carbonyl}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, 993.5 mg of tetrabutylammoniumtert-butyl(2S,4R)-4-cyclopropylmethyl-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1-carboxylatewas afforded (yield 98.9%).

MS m/z 544 [M−Bu₄N]⁻.

All the amount of the tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and purified by octadecyl silica gel columnchromatography to afford 221.9 mg of the title compound (yield 39.5%).

¹H NMR (400 MHz, D₂O) δ 0.01 (m, 2H), 0.37-0.42 (m, 2H), 0.66-0.70 (m,1H), 1.18-1.22 (m, 2H), 1.31-1.41 (m, 1H), 1.42-1.52 (dd, J=13.2 Hz,1H), 1.73-2.06 (m, 5H), 2.15-2.20 (m, 1H), 2.32-2.35 (m, 1H), 3.01-3.05(td, J=2.8, 13.2 Hz, 1H), 3.13-3.16 (d, J=12.0 Hz, 1H), 3.30-3.33 (d,J=12.4 Hz, 1H), 3.46-3.49 (d, J=13.2 Hz, 1H), 3.98-4.02 (dd, 2.8, 12.8Hz, 1H), 4.12-4.14 (d, 8.8 Hz, 1H), 4.18 (br s, 1H); MS m/z 446 [M+H]⁺.

Example 41 Sodium(2S,5R)-7-oxo-N′-{[(2S)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl(2S)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-tert-butyl2-(hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate (730 mg, preparedfollowing procedures analogous to Reference Example 5 and ReferenceExample 6), 643.5 mg of the title compound was afforded (yield 90.9%).

¹H NMR (400 MHz, CDCl₃) δ 1.50 (s, 9H), 1.57-1.66 (m, 1H), 1.89-2.02 (m,2H), 2.21-2.31 (m, 3H), 2.42-2.49 (m, 1H), 2.72-2.81 (m, 1H), 3.06 (m,2H), 3.29 (br s, 1H), 4.01-4.02 (d, J=6.8 Hz, 1H), 4.59-4.62 (m, 1H),4.87-4.90 (d, J=11.6 Hz, 1H), 5.02-5.05 (d, J=11.2 Hz, 1H), 7.34-7.41(m, 5H), 8.25 (br s, 1H), 8.52 (br s, 1H); MS m/z 502 [M+H]⁺.

Step 2 tert-Butyl(2S)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.45 (s, 9H), 1.76 (m, 1H), 1.88-1.99 (m, 1H),2.05-2.19 (m, 2H), 2.22-2.26 (m, 1H), 2.34-2.50 (m, 2H),2.58-2.68 (m,1H), 3.12-3.16 (br d, J=12.4 Hz, 1H), 3.20-3.37 (d, J=12.0 Hz, 1H), 3.70(br s, 1H), 3.94-3.96 (d, J=7.6 Hz, 1H), 4.66-4.69 (d, J=9.2 Hz, 1H); MSm/z 412 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-N′-{[(2S)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(2S)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylatewas afforded (quantitative). All the amount of the tetrabutylammoniumsalt was deprotected with trifluoroacetic acid, and neutralized withsaturated sodium bicarbonate aqueous solution, then purified byoctadecyl silica gel column chromatography to afford 292.6 mg of thetitle compound (yield 55.9%).

¹H NMR (400 MHz, D₂O) δ 1.63-1.70 (m, 1H), 1.76-1.86 (m, 1H), 1.92-2.10(m, 3H), 2.23-2.49 (m, 3H), 3.06-3.09 (d, J=12.0 Hz, 1H), 3.19-3.22 (d,J=12.0 Hz, 1H) , 4.02-4.04 (d, J=11.2 Hz, 1H), 4.07 (br s, 1H),4.27-4.30 (dd, J=5.2, 8.8 Hz, 1H); MS m/z 392 [M−Na+2H]⁺.

Example 42 Sodium(2S,5R)-7-oxo-N′-{[(2R)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1 tert-Butyl(2R)-2-[(2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate

Following a procedure analogous to Example 27, the carboxylic acid (6b,390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl2-(hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate (730 mg, preparedfollowing a procedure analogous to Reference Example 6 from the compounddescribed in Reference Example 4), 431.2 mg of the title compound wasafforded (yield 60.9%).

¹H NMR (400 MHz, CDCl₃) δ 1.44 (s, 9H), 1.56 (m, 1H), 1.81-1.91 (m, 2H),2.14-2.28 (m, 3H), 2.34-2.44 (m, 1H), 2.64-2.73 (m, 1H), 3.00-3.17 (m,2H), 3.20 (s, 1H), 3.92-3.94 (d, J=7.2 Hz, 1H), 4.51-4.53 (d, J=5.6 Hz,1H), 4.82-4.85 (d, J=11.2 Hz, 1H), 4.96-4.99 (d, J=11.6 Hz, 1H),7.29-7.36 (m, 5H), 8.13 (br s, 1H), 8.43 (br s, 1H); MS m/z 502 [M+H]⁺.

Step 2 tert-Butyl(2R)-2-[(2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 412 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-N′-{[(2R)-5-oxopyrrolidin-2-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(2R)-2-[(2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinyl)carbonyl]-5-oxopyrrolidine-1-carboxylatewas afforded (quantitative). MS m/z 490 [M−Bu₄N]⁻.

All the amount of the tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and neutralized with saturated sodium bicarbonateaqueous solution, and then purified by octadecyl silica gel columnchromatography to afford 179.5 mg of the title compound (yield 50.5%).

¹H NMR (400 MHz, D₂O) δ 1.67-1.71 (m, 1H), 1.78-1.86 (m, 1H), 1.92-2.16(m, 3H), 2.26-2.45 (m, 3H), 3.04-3.07 (d, J=12.4 Hz, 1H), 3.19-3.22 (brd, J=12.0 Hz, 1H), 4.01-4.03 (d, J=8.4 Hz, 1H), 4.06 (br s, 1H),4.22-4.28 (dd, J=4.8, 8.8 Hz, 1H); MS m/z 392 [M−Na+2H]⁺.

Example 43 Sodium(2S,5R)—N′-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-N′-(furan-2-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 552 mg, 2.00 mmol) of Example 9 or 16 and furan-2-carbohydrazide(390mg, prepared following a procedure analogous to Reference Example 6from the compound described in Reference Example 3), 291.8 mg of thetitle compound was afforded (yield 37.9%).

¹H NMR (400 MHz, CDCl₃) δ 1.57-1.65 (m, 1H), 1.89-2.02 (m, 2H),2.33-2.38 (m, 1H), 3.10-3.13 (d, J=11.6 Hz, 1H), 3.21-3.24 (d, J=12.0Hz, 1H), 3.31 (s, 1H), 4.07-4.12 (m, 1H), 4.89-4.92 (d, J=11.2 Hz, 1H),5.03-5.06 (d, J=11.2 Hz, 1H), 6.50-6.52 (dd, J=1.6, 3.2 Hz, 1H), 7.17(d, J=3.2 Hz, 1H), 7.32-7.43 (m, 5H), 7.47 (d, J=1.6 Hz, 1H), 8.41 (m,1H), 8.62 (m, 1H); MS m/z 385 [M+H]⁺.

Step 2(2S,5R)—N′-(Furan-2-ylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 295 [M+H]⁺.

Step 3 Sodium(2S,5R)—N′-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N′-(furan-2-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 54.8 mg of the title compound (yield 18.2%).

¹H NMR (400 MHz, D₂O) δ 1.66-1.74 (m, 1H), 1.80-1.97 (m, 2H), 2.08-2.17(m, 1H), 3.11-3.14 (d, J=12.0 Hz, 1H), 3.23-3.26 (d, J=12.4 Hz, 1H),4.09 (m, 2H), 6.51 (d, J=3.6 Hz, 1H), 7.13 (d, J=3.6 Hz, 1H), 7.58 (s,1H); MS m/z 375 [M−Na+2H]⁺.

Example 44 Sodium(2S,5R)—N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and oxazol-4-carbohydrazide(613 mg, prepared following a procedure analogous to Reference Example2), 335.2 mg of the title compound was afforded (yield 61.7%).

¹H NMR (400 MHz, CDCl₃) δ 1.63-1.65 (m, 1H), 1.80-2.00 (m, 2H),2.29-2.37 (m, 1H), 3.08-3.11 (br d, J=13.2 Hz, 1H), 3.15-3.18 (d, J=12.0Hz, 1H), 3.30 (br s, 1H), 4.07-4.08 (d, J=7.2 Hz, 1H), 4.87-4.91 (d,J=11.2 Hz, 1H), 5.02-5.06 (d, J=11.2 Hz, 1H), 7.34-7.42 (m, 5H), 7.88(s, 1H), 8.25 (s, 1H), 8.61 (br s, 1H), 8.73 (br s, 1H); MS m/z 386[M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 296 [M+H]⁺.

Step 3 Sodium(2S,5R)—N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N′-(1,3-oxazol-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 195 mg of the title compound (yield 56.5%).

¹H NMR (400 MHz, D₂O) δ 1.70-1.73 (m, 1H), 1.75-1.88 (m, 1H), 1.93-1.97(m, 1H), 2.06-2.14 (m, 1H), 3.09-3.12 (d, J=12.0 Hz, 1H), 3.18-3.24 (brd, J=12.8 Hz, 1H), 4.04-4.06 (d, J=7.6 Hz, 1H), 4.08-4.09 (m, 1H), 8.05(s, 1H), 8.27 (s, 1H); MS m/z 376 [M−Na+2H]⁺.

Example 45 Sodium(2S,5R)-7-oxo-N′-(pyridine-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-7-oxo-N′-(pyridine-3-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

A solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9or 16 in dehydrated methylene chloride (14.1 mL) was cooled to 0° C.under an argon atmosphere, and isobutyl chloroformate (231.1 mg) wasgradually added so that the temperature does not exceed 0° C. Then,triethylamine (185 mg) was gradually added so that the temperature doesnot exceed 0° C. followed by stirring for 30 minutes, thereby a mixedacid anhydride in the reaction system was prepared. To this reactionmixture was gradually added nicotinic acid hydrazide (580 mg). After theaddition, the temperature was raised to room temperature, followed bystirring for 1 hour. This reaction mixture was washed with 0.5Mhydrochloric acid and saturated brine, and the organic layer was driedover magnesium sulfate, and then distilled off under reduced pressure.The resulting residue was subjected to silica gel column chromatography(hexane/ethyl acetate=4/1-0/1, ethyl acetate/methanol=30/1) to afford439.5 mg of the title compound as a colorless oil (yield 78.8%).

¹H NMR (400 MHz, CD₃OD) δ 1.68-1.75 (m, 1H), 1.88-2.02 (m, 2H),2.25-2.30 (m, 1H), 3.08-3.11 (d, J=12.4 Hz, 1H), 3.28-3.33 (m, 1H), 3.60(br s, 1H), 4.03-4.08 (d, J=12.0 Hz, 1H), 4.90 (d, J=11.2 Hz, 1H), 5.00(d, J=11.2 Hz, 1H), 7.33-7.41 (m, 3H), 7.45-7.48 (m, 2H), 7.54-7.58 (dd,J=5.0, 8.0 Hz, 1H), 8.26-8.29 (dd, J=2.0, 8.0 Hz, 1H), 8.71-8.72 (dd,J=1.2, 4.8 Hz, 1H), 9.00-9.01 (dd, J=0.8, 2.0 Hz, 1H); MS m/z 396[M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-7-oxo-N′-(pyridine-3-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

All the amount of the compound of the above Step 1 was dissolved inmethanol (11 mL), and 10% palladium-carbon (50% water content, 80 mg)was added, followed by stirring under hydrogen atmosphere at roomtemperature for 1 hour. The catalyst of the reaction mixture wasfiltered through Celite, and the solvent was concentrated under reducedpressure to afford 319.7 mg of the title compound (yield 94.3%). MS m/z306 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-N′-(pyridine-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

To a solution of all the amount of the compound of the above Step 2 inpyridine (10.0 mL) was added sulfur trioxide-pyridine complex (796 mg),followed by agitating at room temperature overnight. To the reactionsolution was added methylene chloride, followed by filtration andconcentration under reduced pressure. To the resulting residue was addedtoluene, followed by azeotropy. Thereby, pyridinium(2S,5R)-7-oxo-N′-(pyridine-3-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 193.1 mg of the title compound (yield 45.6%).

¹H NMR (400 MHz, D₂O) δ 1.67-1.75 (m, 1H), 1.80-1.90 (m, 1H), 1.95-1.99(m, 1H), 2.06-2.16 (m, 1H), 3.14-3.18 (d, J=12.4 Hz, 1H), 3.25-3.28 (brd, J=12.0 Hz, 1H), 4.10 (m, 2H), 7.46-7.49 (dd, J=5.2, 8.0 Hz, 1H),8.12-8.14 (d, J=8.0 Hz, 1H), 8.58-8.60 (d, J=5.2 Hz, 1H), 8.81 (s, 1H);MS m/z 386 [M−Na+2H]⁺.

Example 46 Sodium(2S,5R)-7-oxo-N′-(pyridine-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-7-oxo-N′-(pyridine-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and isonicotinic acidhydrazide (580.1 mg, commercially available), the title compound wasafforded (quantitative).

¹H NMR (500 MHz, CDCl₃) δ 1.60 (m, 1H), 1.97-2.04 (m, 2H), 2.34-2.36 (m,1H), 3.15 (m, 2H), 3.35 (br s, 1H), 4.08-4.12 (m, 1H), 4.92-4.94 (d,J=11.0 Hz, 1H), 5.06-5.08 (d, J=11.0 Hz, 1H), 7.26-7.46 (m, 5H),7.67-7.68 (m, 2H), 8.78-8.79 (m, 2H); MS m/z 396 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-7-oxo-N′-(pyridine-4-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). ¹H NMR (400 MHz, CD₃OD) δ 1.69-1.77 (m, 1H), 1.86-1.97(m, 1H), 2.02-2.11 (m, 1H), 2.19-2.31 (m, 1H), 3.16-3.36 (m, 2H), 3.68(br s, 1H), 3.97-3.99 (d, J=6.8 Hz, 1H),7.79-7.80 (d, J=6.0 Hz, 2H),8.65-8.65 (d, J=6.4 Hz, 2H); MS m/z 306 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-N′-(pyridine-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 26, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)-7-oxo-N′-(pyridine-4-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, then purified by octadecyl silica gel column chromatography toafford 255.9 mg of the title compound (yield 44.5%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.73 (m, 1H), 1.78-1.86 (m, 1H), 1.93-197(m, 1H), 2.04-2.14 (m, 1H), 3.12-3.15 (d, J=12.0 Hz, 1H), 3.23-3.26 (d,J=6.8 Hz, 1H), 4.08-4.10 (m, 2H), 7.72-7.73 (d, J=4.4 Hz, 2H),8.60-8.61(d, J=5.2 Hz, 2H); MS m/z 386 [M−Na+2H]⁺.

Example 47 SodiumN,N-dimethyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide Step 12-{[(2S,5R)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 400 mg, 1.44 mmol) of Example 9 or 16 andN,N-dimethylhydrazinecarboxamide (491 mg, prepared following proceduresanalogous to Reference Example 3 and Reference Example 6), 385.2 mg ofthe title compound was afforded (yield 73.6%).

¹H NMR (400 MHz, CDCl₃) δ 1.61 (m, 1H), 1.90-2.02 (m, 2H), 2.32-2.37 (m,1H), 2.95 (s, 6H), 3.05-3.08 (d, J=12.8 Hz, 1H), 3.25 (br s, 1H),3.29-3.32 (d, J=12.0 Hz, 1H), 3.99-4.01 (d, J=6.8 Hz, 1H), 4.87-4.90 (d,J=11.2 Hz, 1H), 5.02-5.05 (d, J=11.2 Hz, 1H), 6.39 (br s, 1H), 7.34-7.41(m, 5H), 8.24 (br s, 1H); MS m/z 361 [M+H]⁺.

Step 22-{[(2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 272 [M+H]⁺.

Step 3 SodiumN,N-dimethyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium2-{[(25,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-dimethylhydrazinecarboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, then purified by octadecyl silica gel column chromatography toafford 305.2 mg of the title compound (yield 77.1%).

¹H NMR (400 MHz, D₂O) δ 1.64-1.72 (m, 1H), 1.76-1.87 (m, 1H), 1.93-1.98(m, 1H), 2.07-2.12 (m, 1H), 2.81 (s, 6H), 3.11-3.14 (d, J=12.4 Hz, 1H),3.20-3.23 (d, J=12.4 Hz, 1H), 4.01-4.03 (d, J=11.2 Hz, 1H), 4.08-4.09(m, 1H); MS m/z 352 [M−Na+2H]⁺.

Example 48 SodiumN,N-diethyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamideStep 12-{[(2S,5R)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N,N-diethylhydrazinecarboxamide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and N,N-diethylhydrazinecarboxamide (656 mg, prepared following procedures analogous toReference Example 3 and Reference Example 6), 108.6 mg of the titlecompound was afforded (yield 19.7%).

¹H NMR (400 MHz, CDCl₃) δ 1.16-1.19 (t, J=7.2 Hz, 6H), 1.55-1.62 (m,1H), 1.89-2.05 (m, 2H), 2.24-2.36 (m, 1H), 3.06-3.09 (br d, J=12.4 Hz,1H), 3.18-3.38 (m, 6H), 4.00-4.02 (br d, J=7.6 Hz, 1H), 4.87-4.90 (d,J=11.2 Hz, 1H), 5.04-5.06 (d, J=11.2 Hz, 1H), 6.36 (br s, 1H), 7.24-7.40(m, 5H), 8.32 (br s, 1H); MS m/z 390 [M+H]⁺.

Step 2 N,N-Diethyl2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 300 [M+H]⁺.

Step 3 Sodium N,N-diethyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium N,N-diethyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 63.0 mg of the title compound (yield 56.4%).

¹H NMR (400 MHz, D₂O) δ 0.97-1.01 (t, J=7.2 Hz, 6H), 1.62-1.68 (m, 1H),1.70-1.85 (m, 1H), 1.92-1.96 (m, 1H), 2.05-2.11 (m, 1H), 3.09-3.22 (m,6H), 3.99-4.01 (d, J=7.8 Hz, 1H), 4.06 (br s, 1H); MS m/z 380[M−Na+2H]⁺.

Example 49 Sodium2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamideStep 12-{[(2SR,5RS)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide

Following a procedure analogous to Example 30, from(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (100 mg, 0.36 mmol) and N-phenylhydrazinecarboxamide (60 mg), 134mg of the title compound was afforded (yield 94%). MS m/z 410 [M+H]⁺.

Step 22-{[(2SR,5RS)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 35 mg of the title compound wasafforded (yield 33%).

¹H NMR (400 MHz, CD₃OD) δ 1.76-1.82 (m, H), 1.91-1.98 (m, H), 2.04-2.08(m, 1H), 2.25-2.31 (m, 1H), 3.17 (d, J=3.0, 1H), 3.25 (d, J=3.0, 1H),3.70 (br. s, 1H), 4.00 (d, J=1.8, 1H), 7.00 (dd, J=2.1, 2.2, 1H),7.23-7.28 (m, 1H), 7.39-7.42 (m, 1H); m/z 320 [M+H]⁺.

Step 3 Sodium2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide

Following a procedure analogous to Example 30, pyridinium2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}-N-phenylhydrazinecarboxamide obtained from the compound (30 mg, 0.10 mmol) of the aboveStep 2 was neutralized with saturated sodium bicarbonate aqueoussolution, and purified by octadecyl silica gel column chromatography toafford 19 mg of the title compound (yield 43%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.73 (m, 1H), 1.78-1.88 (m, 1H), 1.93-1.97(m, 1H), 2.06-2.12 (m, 1H), 3.08 (d, J=3.0, 1H), 3.22 (d, J=3.2, 1H),4.06 (m, 2H), 7.18-7.27 (m, 5H); MS m/z 400 [M−Na+2H]⁺.

Example 50 Sodium(2S,5R)—N′-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-N′-(morpholin-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 andmorpholine-4-carbohydrazide (584.3 mg, prepared following proceduresanalogous to Reference Example 3 and Reference Example 6), 323 mg of thetitle compound was afforded (yield 56.8%).

¹H NMR (400 MHz, CDCl₃) δ 1.58-1.65 (m, 1H), 1.91-2.02 (m, 2H),2.32-2.37 (m, 1H), 3.06-3.09 (d, J=11.6 Hz, 1H), 3.24-3.27 (m, 1 H),3.36-3.46 (m, 4H), 3.63-3.69 (m, 4H), 4.00-4.02 (br d, J=7.6 Hz, 1H),4.88-4.90 (d, J=11.2 Hz, 1H), 5.02-5.05 (d, J=11.2 Hz, 1H), 6.52 (br s,1H), 7.34-7.42 (m, 5H), 8.30 (br s, 1H); MS m/z 404 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N′-(morpholin-4-ylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 314 [M+H]⁺.

Step 3 Sodium(2S,5R)—N′-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N′-(morpholin-4-ylcarbonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 152 mg of the title compound (yield 45.7%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.72 (m, 1H), 1.78-1.88 (m, 1H), 1.94-1.98(m, 1H), 2.07-2.13 (m, 1H), 3.10-3.13 (d, J=12.0 Hz, 1H), 3.21-3.24 (d,J=12.0 Hz, 1H), 3.32-3.35 (m, 4H), 3.61-3.63 (m, 4H), 4.02-4.04 (d,J=7.6 Hz, 1H), 4.08 (br s, 1H); MS m/z 394 [M−Na+2H]⁺.

Example 51 Sodium methyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylateStep 1 Methyl2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following a procedure analogous to Example 17, from the carboxylic acid(6b, 1.30 g, 4.71 mmol) of Example 9 or 16 and methyl carbazate (538mg), 1.64 g of the title compound was afforded (quantitative).

[α]_(D) ²⁰+53.2° (c 0.60, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.56-1.68(m, 1H), 1.90-2.08 (m, 2H), 2.30-2.40 (m, 1H), 3.02-3.20 (m, 2H), 3.30(br s, 1H), 3.76 (br s, 3H), 4.01 (d, J=7.2 Hz, 1H), 4.91 (d, J=11.4 Hz,1H), 5.06 (d, J=11.4 Hz, 1H), 6.59 (br s, 1H), 7.33-7.46 (m, 5H), 8.23(br d, J=2.4 Hz, 1H); MS m/z 349 [M+H]⁺.

Step 2 Methyl2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following a procedure analogous to Example 17, from the compound (2.11g, 6.06 mmol) of the above Step 1, 1.22 g of the title compound wasafforded (yield 78%).

[α]_(D) ²⁰−34.8° (c 0.57, MeOH); ¹H NMR (400 MHz, CD₃OD) δ 1.70-1.79 (m,1H), 1.87-1.98 (m, 1H), 2.02-2.12 (m, 1H), 2.26 (br dd, J=14.6, 6.6 Hz,1H), 3.12-3.25 (m, 2H), 3.67-3.75 (m, 1H), 3.72 (s, 3H), 3.92 (br d,J=7.6 Hz, 1H); MS m/z 259 [M+H]⁺.

Step 3 Sodium methyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

To a solution of the compound (1.21 g, 4.70 mmol) of the above Step 2 inpyridine (30 mL) was added sulfur trioxide-pyridine complex (3.39 g),followed by agitating at room temperature overnight. To the reactionsolution was added methylene chloride, followed by filtration andconcentration under reduced pressure. To the resulting residue was addedtoluene, followed by azeotropy and concentration to dryness. A saturatedsodium dihydrogen phosphate aqueous solution (100 mL) was added, theaqueous layer was washed with ethyl acetate, followed by addingtetrabutylammonium hydrogen sulfate (1.93 g) and ethyl acetate (10 mL),and agitating for 10 minutes. The aqueous layer was extracted with ethylacetate. Subsequently, the resulting organic layer was dried overanhydrous sodium sulfate, filtrated, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (methylene chloride/acetone/triethylamine=49/49/2) toafford 2.09 g of tetrabutylammonium methyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate.

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 12H), 1.45 (sex, J=7.4 Hz,8H), 1.60-1.75 (m, 9H), 1.86-1.98 (m, 1H), 2.15-2.24 (m, 1H), 2.37 (brdd, J=15.0, 7.0 Hz, 1H), 3.05-3.20 (m, 1H), 3.25-3.34 (m, 8H), 3.38 (brd, J=11.6 Hz, 1H), 3.78 (s, 3H), 3.99 (d, J=7.6 Hz, 1H), 4.35 (br s,1H), 6.55 (br s, 1H), 8.28 (br s, 1H); MS m/z 339 [M−Bu₄N+2H]⁺.

After all the amount of the tetrabutylammonium salt was treated withDOWEX (Na type), the resulting crude product was purified by SP207(acetonitrile/water=0/100-5/95) and lyophilized to afford 880 mg of thetitle compound (yield 52%).

[α]_(D) ²¹−37.6° (c 0.36, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.62-1.73 (m,1H), 1.76-1.88 (m, 1H), 1.92-2.00 (m, 1H), 2.08 (br dd, J=15.6, 6.8 Hz,1H), 3.04 (br d, J=12.0 Hz, 1H), 3.21 (br d, J=12.0 Hz, 1H), 3.61 (s,3H), 4.02 (br d, J=7.6 Hz, 1H), 4.04-4.10 (m, 1H); MS m/z 339[M−Na+2H]⁺; Na content 7.9%.

Example 52 Sodium ethyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylateStep 1 Ethyl2-{[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following a procedure analogous to Example 17, from the carboxylic acid(6b, 352 mg, 1.27 mmol) of Example 9 or 16 and ethyl carbazate (184 mg),388 mg of the title compound was afforded (yield 84%).

[α]_(D) ²⁰+53.4° (c 0.64, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.28 (t,J=7.2 Hz, 3H), 1.55-1.66 (m, 1H), 1.90-2.05 (m, 2H), 2.31-2.40 (m, 1H),3.03-3.17 (m, 2H), 3.27-3.32 (m, 1H), 4.01 (d, J=7.2 Hz, 1H), 4.20 (q,J=7.2 Hz, 2H), 4.92 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 6.47(br s, 1H), 7.35-7.46 (m, 5H), 8.19 (br s, 1H); MS m/z 363 [M+H]⁺.

Step 2 Ethyl2-{[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following a procedure analogous to Example 17, from the compound (369mg, 1.02 mmol) of the above Step 1, the title compound was afforded(quantitative).

[α]_(D) ²⁰−29.9° (c 0.62, MeOH); ¹H NMR (400 MHz, CD₃OD) δ 1.27 (br t,J=7.2 Hz, 3H), 1.68-1.82 (m, 1H), 1.87-1.99 (m, 1H), 2.01-2.15 (m, 1H),2.27 (br dd, J=15.0, 6.6 Hz, 1H), 3.11-3.25 (m, 2H), 3.70 (br s, 1H),3.92 (br d, J=7.2 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H); MS m/z 273 [M+H]⁺.

Step 3 Sodium ethyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium ethyl2-{[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylatewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by DIAION HP21 (MITSUBISHI CHEMICAL) columnchromatography to afford 108 mg of the title compound (2 steps, yield29%).

[α]_(D) ²¹−34.5° (c 0.52, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.11 (br t,J=7.2 Hz, 3H), 1.61-1.72 (m, 1H), 1.75-1.88 (m, 1H), 1.90-2.00 (m, 1H),2.08 (br dd, J=15.2, 7.2 Hz, 1H), 3.03 (br d, J=12.0 Hz, 1H), 3.21 (brd, J=12.0 Hz, 1H), 4.05 (br d, J=7.6 Hz, 1H), 4.04 (q, J=7.2 Hz, 2H),4.07 (br s, 1H); MS m/z 353 [M−Na+2H]⁺.

Example 53 Sodium tert-butyl2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate Step 1 tert-Butyl{[(2SR,5RS)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following a procedure analogous to Example 18, from(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (280 mg, 1.01 mmol) and tert-butyl hydrazinecarboxylate (147 mg),299 mg of the title compound was afforded (yield 68%).

¹H NMR (400 MHz, CDCl₃) δ 1.33 (s, 9H), 1.49-1.55 (m, 1H), 1.74-1.91 (m,2H), 2.18-2.23 (m, 1H), 2.96 (m, 2H), 3.18 (br s, 1H), 3.78 (d, J=1.9,1H), 4.78 (d, J=2.8, 1H), 4.93 (d, J=2.8, 1H), 6.69 (s, 1H), 7.19-7.32(m, 5H), 8.31 (s, 1H), MS m/z 391 [M+H]⁺.

Step 2 tert-Butyl2-{[(2SR,5RS)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following a procedure analogous to Example 17, from the compound (310mg, 0.79 mmol) of the above Step 1, 200 mg of the title compound wasafforded (yield 84%).

MS m/z 301 [M+H]⁺.

Step 3 Sodium tert-butyl{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylate

Following a procedure analogous to Example 18, pyridinium tert-butyl2-{[(2SR,5RS)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}hydrazinecarboxylateobtained from the compound (118 mg, 0.39 mmol) of the above Step 2 wasneutralized with saturated sodium bicarbonate aqueous solution, and thenpurified by octadecyl silica gel column chromatography to afford 73 mgof the title compound (yield 46%).

¹H NMR (400 MHz, D₂O) δ 1.47 (s, 9 H), 1.84-1.88 (m, 1H), 1.93-2.03 (m,1H), 2.10-2.14 (m, 1H), 2.22-2.28 (m, 1H), 3.20 (d, J=3.0, 1H), 3.38 (d,J=3.1, 1H), 4.16 (d, J=1.7, 1H), 4.24 (br s, 1H); MS m/z 379 [M−Na]⁻.

Example 54 Sodium(2S,5R)—N′-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazideStep 1(2S,5R)-6-Benzyloxy-N′-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from the carboxylic acid(6b, 345 mg, 1.25 mmol) of Example 9 or 16 and methanesulfonyl hydrazide(193 mg), 359 mg of the title compound was afforded (yield 78%).

[α]_(D) ²⁰+22.8° (c 0.55, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.54-1.66(m, 1H), 1.96-2.09 (m, 2H), 2.26-2.36 (m, 1H), 2.74 (d, J=12.0 Hz, 1H),3.02 (s, 3H), 3.11 (br d, J=12.0 Hz, 1H), 3.31-3.34 (m, 1H), 4.08 (d,J=7.6 Hz, 1H), 4.91 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz, 1H), 6.78(br s, 1H), 7.35-7.48 (m, 5H), 8.71 (br s, 1H); MS m/z 369 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N′-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 17, from the compound (347mg, 0.943 mmol) of the above Step 1, 259 mg of the title compound wasafforded (quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.71-1.84 (m, 1H), 1.88-2.01 (m, 1H),2.02-2.15 (m, 1H), 2.20-2.30 (m, 1H), 2.98-3.09 (m, 1H), 3.01 (s, 3H),3.15 (br d, J=10.4 Hz, 1H), 3.67-3.75 (m, 1H), 3.93 (br d, J=7.6 Hz,1H); MS m/z 279 [M+H]⁺.

Step 3 Sodium(2S,5R)—N′-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide

Following a procedure analogous to Example 22, from the compound (253mg, 0.909 mmol) of the above Step 2, pyridinium(2S,5R)—N′-(methylsulfonyl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 65.9 mg of the title compound (yield 19%).

[α]_(D) ²⁰−44.1° (c 0.10, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.63-1.72 (m,1H), 1.75-1.88 (m, 1H), 1.90-2.00 (m, 1H), 2.07 (br dd, J=15.4, 7.0 Hz,1H), 2.94 (d, J=12.0 Hz, 1H), 2.99 (s, 3H), 3.20 (br d, J=12.0 Hz, 1H),4.01 (d, J=7.2 Hz, 1H), 4.03-4.09 (m, 1H); MS m/z 359 [M−Na+2H]⁺.

Example 55 Sodium(2SR,5RS)-N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2SR,5RS)-6-Benzyloxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (142 mg, 0.513 mmol) in methylene chloride (3.5 mL) were addedtriethylamine (226 μl), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimidehydrochloride (125 mg), 1-hydroxybenzotriazole.monohydrate (100 mg), andmorpholin-4-amine (62.7 μl), followed by agitating at room temperatureovernight. The reaction solution was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate) to afford 149 mg of the title compound(yield 80%).

¹H NMR (400 MHz, CDCl₃) δ 1.57-1.66 (m, 1H), 1.86-2.06 (m, 2H), 2.37 (brdd, J=14.2, 6.8 Hz, 1H), 2.72 (d, J=11.8 Hz, 1H), 2.74-2.88 (m, 4H),3.01 (br d, J=11.8 Hz, 1H), 3.28-3.33 (m, 1H), 3.81 (t, J=4.6 Hz, 4H),3.90 (br d, J=7.6 Hz, 1H), 4.91 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz,1H), 7.32-7.48 (m, 6H); MS m/z 361 [M+H]⁺.

Step 2(2SR,5RS)-6-Hydroxy-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from the compound (170mg, 0.471 mmol) of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.74-1.84 (m, 1H), 1.85-1.97 (m, 1H),2.02-2.11 (m, 1H), 2.21 (br dd, J=14.8, 7.2 Hz, 1H), 2.81 (br t, J=4.4Hz, 4H), 3.01 (d, J=11.6 Hz, 1H), 3.12 (br d, J=11.6 Hz, 1H), 3.69 (brs, 1H), 3.76 (br t, J=4.4 Hz, 4H), 3.81 (br d, J=7.6 Hz, 1H); MS m/z 271[M+H]⁺.

Step 3 Sodium(2SR,5RS)—N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2SR,5RS)—N-(morpholin-4-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by SEPABEADS SP207 (MITSUBISHI CHEMICAL)column chromatography to afford 104 mg of the title compound (2 steps,yield 63%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.85 (m, 2H), 1.90-1.99 (m, 1H), 2.00-2.08(m, 1H), 2.68-2.80 (m, 4H), 3.97 (d, J=12.0 Hz, 1H), 3.18 (br d, J=12.0Hz, 1H), 3.70 (br t, J=4.6 Hz, 4H), 3.89 (br d, J=7.0 Hz, 1H), 4.07 (brdd, J=5.6, 2.8 Hz, 1H); MS m/z 351 [M−Na+2H]⁺.

Example 56 Sodium(2S,5R)—N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of the carboxylic acid (6b, 965 mg, 3.49 mmol) of Example9 or 16 in tetrahydrofuran (20 mL) were added triethylamine (1.95 mL),N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (802 mg),1-hydroxybenzotriazole monohydrate (658 mg), and O-methylhydroxylaminehydrochloride (363 mg), followed by agitating to room temperatureovernight. The reaction solution was concentrated under reducedpressure, and the resulting residue was purified by silica gel columnchromatography (hexane/ethyl acetate=9/1-0/10) to afford 773 mg of thetitle compound (yield 72%).

[α]_(D) ²⁰−19.8° (c 0.60, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.60-1.71(m, 1H), 1.88-2.07 (m, 2H), 2.32 (br dd J=14.2, 7.4 Hz, 1H), 2.80 (d,J=11.6 Hz, 1H), 3.00 (br d, J=11.6 Hz, 1H), 3.30-3.35 (m, 1H), 3.78 (s,3H), 3.94 (d, J=7.6 Hz, 1H), 4.90 (d, J=11.6 Hz, 1H), 5.05 (d, J=11.6Hz, 1H), 7.34-7.46 (m, 5H), 9.22 (br s, 1H); MS m/z 306 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from the compound (770mg, 2.52 mmol) of the above Step 1, 486 mg of the title compound wasafforded (yield 90%).

[α]_(D) ²⁰−76.8° (c 0.34, MeOH); ¹H NMR (400 MHz, CD₃OD) δ 1.74-1.84 (m,1H), 1.86-1.98 (m, 1H), 2.03-2.13 (m, 1H), 2.20 (br dd J=15.0, 7.0 Hz,1H), 3.05 (d, J=11.8 Hz, 1H), 3.12 (br d, J=11.8 Hz, 1H), 3.66-3.74 (m,1H), 3.71 (s, 3H), 3.82 (br d, J=7.6 Hz, 1H); MS m/z 216 [M+H]⁺.

Step 3 Sodium(2S,5R)—N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from the compound (483mg, 2.24 mmol) of the above Step 2, 963 mg of tetrabutylammonium(2S,5R)—N-methoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded.

¹H NMR (400 MHz, CDCl₃) δ 0.93 (t, J=7.4 Hz, 12H), 1.37 (sex, J=7.4 Hz,8H), 1.53-1.72 (m, 9H), 1.77-1.90 (m, 1H), 2.05-2.15 (m, 1H), 2.27 (brdd, J=14.8, 6.4 Hz, 1H), 2.84 (d, J=11.6 Hz, 1H), 3.14-3.31 (m, 9H),3.73 (s, 3H), 3.87 (br d, J=7.6 Hz, 1H), 4.25 (br s, 1H), 9.32 (br s,1H); MS m/z 296 [M−Na+2H]⁺.

All the amount of the tetrabutylammonium salt was subjected to ionexchange by DOWEX (Na type), and then purified by octadecyl silica gelcolumn chromatography to afford 401 mg of the title compound (yield56%).

[α]_(D) ²⁰−49.0° (c 0.85, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.66-1.87 (m,2H), 1.91-2.07 (m, 2H), 3.02(d, J=12.0 Hz, 1H), 3.18 (br d, J=12.0 Hz,1H), 3.62 (s, 3H), 3.92 (dd, J=8.0, 2.4 Hz, 1H), 4.07 (dd, J=6.0, 2.8Hz, 1H); MS m/z 296 [M+H]⁺; Na content 10.9%.

Example 57 Sodium(2SR,5RS)—N-ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2SR,5RS)-6-Benzyloxy-N-ethoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 27, from(2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (150 mg, 0.58 mmol) and O-ethylhydroxylamine hydrochloride (85 mg),95 mg of the title compound was afforded (yield 39%). MS m/z 320 [M+H]+.

Step 2 (2SR,5RS)—N-Ethoxy6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 88 mg of the title compound wasafforded (yield 96%).

Step 3 Sodium(2SR,5RS)-N-ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 18, from all the amount ofthe compound of the above Step 2, pyridinium(2SR,5RS)—N-ethoxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 30 mg of the title compound (yield 24%).

¹H NMR (400 MHz, D₂O) δ 1.09 (t, J=1.7, 3H), 1.66-1.86 (m, 2H),1.91-2.02 (m, 2H), 3.00 (d, J=3.0, 1H), 3.17 (d, J=2.9, 1H), 3.84 (q,J=1.7, 2H), 3.92 (d, J=1.7, 1H), 4.06 (m, 1H); MS m/z 308 [M−Na]⁻.

Example 58 Sodium(2S,5R)—N-(cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-N-(cyclobutylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 379 mg, 1.37 mmol) of Example 9 or 16 andO-(cyclobutylmethyl)hydroxylamine (274 mg, prepared following aprocedure analogous to Reference Example 7 and Reference Example 15),359.4 mg of the title compound was afforded (yield 73%).

¹H NMR (400 MHz, CDCl₃) δ 1.55-2.15 (m, 9H), 2.28-2.39 (m, 1H),2.59-2.72 (m, 1H), 2.77 (d, J=11.6 Hz, 1H), 3.00 (br d, J=11.6 Hz, 1H),3.26-3.34 (m, 1H), 3.83-3.89 (m, 1H), 3.90-3.97 (m, 2H), 4.90 (d, J=11.4Hz, 1H), 5.05 (d, J=11.4 Hz, 1H), 7.34-7.46 (m, 5H), 8.98 (s, 1H); MSm/z 360 [M+H]⁺.

Step 2(2S,5R)—N-(Cyclobutylmethoxy)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 270 [M+H]⁺.

Step 3 Sodium(2S,5R)—N-(cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 18, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N-(cyclobutylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 157.8 mg of the title compound (2 steps, yield42%).

¹H NMR (400 MHz, D₂O) δ 1.55-1.86 (m, 6H), 1.88-2.07 (m, 4H), 2.46-2.57(m, 1H), 3.00 (d, J=12.0 Hz, 1H), 3.18 (br d, J=12.0 Hz, 1H), 3.79 (d,J=7.2 Hz, 2H), 3.87-3.94 (m, 1H), 4.05-4.10 (m, 1H); MS m/z 350[M−Na+2H]⁺.

Example 59(2S,5R)—N-(2-Aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-059)

Step 1 tert-Butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate

To a solution of the carboxylic acid (6b, 1.34 g, 4.87 mmol) of Example9 or 16 in methylene chloride (35 mL) were added triethylamine (2.71mL), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41g), 1-hydroxybenzotriazole monohydrate (1.15 g), and tert-butyl2-(aminooxy)ethylcarbamate (1.12 g) described in Reference Example 9,followed by agitating at room temperature overnight. To the residueresulting from concentrating the reaction solution under reducedpressure was added water, followed by extracting with ethyl acetate. Theresulting organic layer was washed with 0.1M hydrochloric acid,saturated sodium bicarbonate aqueous solution, and a saturated sodiumchloride aqueous solution, dried over anhydrous sodium sulfate,filtrated, and concentrated. The resulting residue was purified bysilica gel column chromatography (hexane/ethyl acetate=8/2-0/10) toafford 1.77 g of the title compound (yield 84%).

[α]_(D) ²⁰−0.08° (c 0.29, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.44 (s,9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d,J=11.6 Hz, 1H), 3.03 (br d, J=11.6 Hz, 1H), 3.24-3.47 (m, 3H), 3.84-4.01(m, 3H), 4.90 (d, J=11.6 Hz, 1H), 5.05 (d, J=11.6 Hz, 1H), 5.44 (br s,1H), 7.34-7.48 (m, 5H), 9.37 (br s, 1H); MS m/z 435 [M+H]⁺; enantiomericexcess 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1,UV 210 nm, flow rate 1 mL/min., retention time 4.95 min. (2R,5S), 6.70min. (2S,5R).

Step 2 tert-Butyl{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate

To a solution of the compound (3.91 g, 9.01 mmol) of the above Step 1 inmethanol (80 mL) was added 10% palladium carbon catalyst (50% watercontent, 803 mg), followed by agitating under hydrogen atmosphere for 45minutes. The reaction solution was filtered through Celite andconcentrated under reduced pressure to afford 3.11 g of the titlecompound (quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.44 (s, 9H), 1.73-1.83 (m, 1H), 1.86-1.99 (m,1H), 2.01-2.12 (m, 1H), 2.22 (br dd, J=15.0, 7.0 Hz, 1H), 3.03 (d,J=12.0 Hz, 1H), 3.12 (br d, J=12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71(m, 1H), 3.82-3.91 (m, 3H); MS m/z 345 [M+H]⁺.

Step 3(2S,5R)—N-(2-Aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of the compound (3.09 g, 8.97 mmol) of the above Step 2 inmethylene chloride (80 mL) were added 2,6-lutidine (3.20 mL) and sulfurtrioxide-pyridine complex (3.58 g), followed by agitating at roomtemperature overnight. The reaction solution was poured intohalf-saturated sodium bicarbonate aqueous solution, and the aqueouslayer was washed with chloroform. To the aqueous layer were addedtetrabutylammonium hydrogen sulfate (3.47 g) and chloroform (30 mL),followed by agitating for 10 minutes. The aqueous layer was extractedwith chloroform, and the resulting organic layer was dried overanhydrous sodium sulfate, filtrated, and concentrated under reducedpressure to afford 5.46 g of tetrabutylammonium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(yield 91%).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 12H), 1.37-1.54 (m, 8H),1.45 (s, 9H), 1.57-1.80 (m, 9H), 1.85-1.98 (m, 1H), 2.14-2.24 (m, 1H),2.30-2.39 (m, 1H), 2.83 (d, J=11.6 Hz, 1H), 3.20-3.50 (m, 11H),3.85-3.99 (m, 3H), 4.33-4.38 (m, 1H), 5.51 (br s, 1H), 9.44 (br s, 1H);MS m/z 425 [M−Bu₄N+2H]⁺.

To a solution of the tetrabutylammonium salt (5.20 g, 7.82 mmol) inmethylene chloride (25 mL) was added trifluoroacetic acid (25 mL) underice-cooling, followed by agitating at 0° C. for 1 hour. The reactionsolution was concentrated under reduced pressure. The resulting residuewas washed with diethyl ether, and adjusted to pH 7 with a sodiumbicarbonate aqueous solution, and then purified by octadecyl silica gelcolumn chromatography (water), and then lyophilized to afford 1.44 g ofthe title compound (yield 57%).

[α]_(D) ²⁴−63.5° (c 0.83, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.66-1.76 (m,1H), 1.76-1.88 (m, 1H), 1.91-2.00 (m, 1H), 2.00-2.08 (m, 1H), 3.02(d,J=12.0 Hz, 1H), 3.15 (t, J=5.0 Hz, 2H), 3.18 (br d, J=12.0 Hz, 1H), 3.95(dd, J=7.8, 2.2 Hz, 1H), 4.04 (t, J=5.0 Hz, 2H), 4.07 (dd, J=6.4, 3.2Hz, 1H); MS m/z 325 [M+H]⁺.

Example 60 Sodium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(II-060)

From the compound (1.700 g, 4.938 mmol) of Step 2 of Example 59,pyridinium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamatewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 926.7 mg of the title compound (yield 43.6%).

¹H NMR (400 MHz, D₂O) δ 1.28 (s, 9H), 1.68-1.83 (m, 2H), 1.92-2.07 (m,2H), 3.00-3.03 (d, J=12.8 Hz, 1H), 3.16-3.22 (m, 3H), 3.81-3.84 (d,J=4.8 Hz, 2H), 3.90-3.92 (d, J=6.4 Hz, 1H), 4.06-4.07 (br s, 1H); MS m/z423 [M−Na]⁻.

Example 61(2S,5R)—N-[2-(Methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-061)

Step 1tert-Butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(2-(aminooxy)ethyl)(methyl)carbamate (436 mg) described in ReferenceExample 16, 347.8 mg of the title compound was afforded (yield 55%).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 1.58-1.70 (m, 1H), 1.88-2.07 (m,2H), 2.25-2.36 (m, 1H), 2.70-3.08 (m, 2H), 2.88 (s, 3H), 3.23-3.41 (m,2H), 3.51-3.68 (m, 1H), 3.83-4.10 (m, 3H), 4.90 (d, J=11.4 Hz, 1H), 5.06(d, J=11.4 Hz, 1H), 7.32-7.47 (m, 5H), 10.11 (br s, 1H); MS m/z 449[M+H]⁺.

Step 2 tert-butyl{2-[({[(2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.46 (s, 9H), 1.73-1.83 (m, 1H), 1.86-2.00 (m,1H), 2.01-2.13 (m, 1H), 2.14-2.28 (m, 1H), 2.93 (s, 3H), 3.04 (d, J=10.8Hz, 1H), 3.08-3.18 (m, 1H), 3.43-3.55 (m, 2H), 3.65-3.72 (m, 1H),3.79-3.88 (m, 1H), 3.92-4.05 (m, 2H); MS m/z 359 [M+H]⁺.

Step 3(2S,5R)—N-[2-(Methylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}methylcarbamatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.2 Hz, 12H), 1.36-1.53 (m, 8H),1.47 (s, 9H), 1.57-1.77 (m, 9H), 1.83-1.98(m, 1H), 2.13-2.25 (m, 1H),2.28-2.40 (m, 1H), 2.82-2.96 (m, 4H), 3.22-3.42 (m, 11H), 3.60-4.08 (m,3H), 4.34 (br s, 1H), 10.15 (br s, 1H); MS m/z 437 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and purified by octadecyl silica gel columnchromatography to afford 149.4 mg of the title compound (3 steps,yield57%).

¹H NMR (500 MHz, D₂O) δ 1.73-1.97 (m, 2H), 1.98-2.07 (m, 1H), 2.08-2.18(m, 1H), 2.74 (s, 3H), 3.09 (d, J=12.0 Hz, 1H), 3.21-3.32 (m, 3H), 4.04(dd, J=7.5, 2.0 Hz, 1H), 4.10-4.23 (m, 3H); MS m/z 337 [M−H]⁻.

Example 62(2S,5R)—N-[2-(Ethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1tert-Butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}ethylcarbamate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg, 1.50 mmol) of Example 9 or 16 and tert-butyl(2-(aminooxy)ethyl) (ethyl)carbamate (744 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 15),541.6 mg of the title compound was afforded (yield 78%).

¹H NMR (400 MHz, CDCl₃) δ 1.11 (t, J=7.2 Hz, 3H), 1.46 (s, 9H),1.58-1.74 (m, 1H), 1.89-2.08 (m, 2H), 2.24-2.38 (m, 1H), 2.72-2.91 (m,1H), 2.92-3.11 (m, 1H), 3.12-3.42 (m, 4H), 3.43-3.66 (m, 1H), 3.85-4.05(m, 3H), 4.90 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz, 1H), 7.33-7.47 (m,5H), 10.18 (br s, 1H); MS m/z 463 [M+H]⁺.

Step 2 tert-Butylethyl{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.22 (t, J=7.0 Hz, 3H), 1.46 (s, 9H),1.73-1.84 (m, 1H), 1.86-1.98 (m, 1H), 2.02-2.12 (m, 1H), 2.14-2.27 (m,1H), 3.04 (d, J=11.6 Hz, 1H), 3.09-3.18 (m, 1H), 3.25-3.37 (m, 2H),3.43-3.54 (m, 2H), 3.66-3.72 (m, 1H), 3.79-3.88 (m, 1H), 3.89-4.03 (m,2H); MS m/z 373 [M+H]⁺.

Step 3(2S,5R)—N-[2-(Ethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}ethylcarbamatewas afforded (quantitative). MS m/z 451 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid and purified by octadecyl silica gel columnchromatography to afford 166.6 mg of the title compound (3 steps, yield40%).

¹H NMR (500 MHz, D₂O) δ 1.25 (t, J=7.3 Hz, 3H), 1.73-1.83 (m, 1H),1.84-1.95 (m, 1H), 1.97-2.15 (m, 2H), 3.05-3.13 (m, 3H), 3.22-3.29 (m,3H), 3.99-4.04 (m, 1H), 4.10-4.17 (m, 3H); MS m/z 353 [M+H]⁺.

Example 63(2S,5R)-7-Oxo-N-[2-(propylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propylcarbamate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg, 1.50 mmol) of Example 9 or 16 and tert-butyl(2-(aminooxy)ethyl)(propyl)carbamate (801 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 15),552.2 mg of the title compound was afforded (yield 77%).

¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.53(sext, J=7.2 Hz, 2H), 1.58-1.73 (m, 1H), 1.87-2.07 (m, 2H), 2.23-2.36(m, 1H), 2.83 (d, J=11.2 Hz, 1H), 2.96-3.40 (m, 5H), 3.44-3.64 (m, 1H),3.83-4.07 (m, 3H), 4.90 (d, J=11.4 Hz, 1H), 5.06 (d, J=11.4 Hz, 1H),7.32-7.48 (m, 5H), 10.20 (br s, 1H); MS m/z 477 [M+H]⁺.

Step 2 tert-Butyl{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propylcarbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 436.7 mg of the title compound wasafforded (yield 97%).

¹H NMR (400 MHz, CD₃OD) δ 0.89 (t, J=7.5 Hz, 3H), 1.40-1.61 (m, 2H),1.46 (s, 9H), 1.66-2.00 (m, 2H), 2.02-2.28 (m, 2H), 3.04 (d, J=11.6 Hz,1H), 3.09-3.19 (m, 1H), 3.24 (t, J=7.2 Hz, 2H), 3.42-3.56 (m, 2H),3.62-3.74 (m, 1H), 3.79-4.05 (m, 3H); MS m/z 387 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[2-(propylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propylcarbamatewas afforded (quantitative). MS m/z 465 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and purified by octadecyl silica gel columnchromatography to afford 226.9 mg of the title compound (3 steps, yield53%).

¹H NMR (500 MHz, D₂O) δ 0.92 (t, J=7.5 Hz, 3H), 1.66 (sext, J=7.5 Hz,2H),1.74-1.82 (m, 1H), 1.83-1.94 (m, 1H), 1.97-2.13 (m, 2H), 3.00 (t,J=7.5 Hz, 2H), 3.11 (d, J=12.0 Hz, 1H), 3.21-3.29 (m, 3H), 3.96-4.03 (m,1H), 4.09-4.17 (m, 3H); MS m/z 367 [M+H]⁺.

Example 64(2S,5R)-7-Oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-064)

Step 1 tert-Butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg, 1.50 mmol) of Example 9 or 16 and tert-butyl(2-(aminooxy)ethyl)(isopropyl)carbamate (596 mg) described in ReferenceExample 17, 578.4 mg of the title compound was afforded (yield 81%).

¹H NMR (400 MHz, CDCl₃) δ 1.15 (d, J=6.8 Hz, 6H), 1.46 (s, 9H),1.55-1.70 (m, 1H), 1.89-2.07 (m, 2H), 2.25-2.37 (m, 1H), 2.73-2.90 (m,1H), 2.98-3.08 (m, 1H), 3.22-3.38 (m, 2H), 3.40-3.60 (m, 1H), 3.83-4.06(m, 4H), 4.90 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.35-7.46 (m,5H), 10.29 (br s, 1H); MS m/z 477 [M+H]⁺.

Step 2 tert-Butyl{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.09-1.23 (m, 6H), 1.46 (s, 9H), 1.73-2.27 (m,4H), 3.06 (d, J=11.6 Hz, 1H), 3.08-3.50 (m, 4H), 3.64-3.73 (m, 1H),3.79-3.98 (m, 3H); MS m/z 387 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[2-(propan-2-ylamino)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}propan-2-ylcarbamatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (d, J=7.4 Hz, 12H), 1.10-1.20 (m, 6H),1.33-1.77 (m, 17H), 1.46 (s, 9H), 1.84-1.97 (m, 1H), 2.12-2.25 (m, 1H),2.28-2.40 (m, 1H), 2.79-2.95 (m, 1H), 3.17-3.45 (m, 9H), 3.50-3.67 (m,1H), 3.80-4.07 (m, 5H), 4.34 (br s, 1H), 10.36 (br s, 1H); MS m/z 465[M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and purified by octadecyl silica gel columnchromatography to afford 252.1 mg of the title compound (3 steps, yield57%).

¹H NMR (500 MHz, D₂O) δ 1.28 (d, J=6.5 Hz, 6H),1.74-1.83 (m, 1H),1.85-1.96 (m, 1H), 1.98-2.14 (m, 2H), 3.11 (d, J=12.5 Hz, 1H), 3.22-3.30(m, 3H), 3.40 (quint, J=6.5 Hz, 1H), 4.01 (br d, J=5.5 Hz, 1H),4.09-4.18 (m, 3H); MS m/z 367 [M+H]⁺.

Example 65(2S,5R)—N-[2-(Dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Step 1(2S,5R)-6-Benzyloxy-N-[2-(dimethylamino)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

A solution of the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9or 16 in dehydrated methylene chloride (10 mL) was cooled to 0° C. underan argon atmosphere, followed by adding dropwise isobutyl chloroformate(289 μL, 2.20 mmol). Then, triethylamine (293 μL) was added, followed bystirring for 30 minutes. Thereby, a mixed acid anhydride was prepared inthe reaction system. To this reaction mixture were gradually added2-(aminooxy)-N,N-dimethylethanamine dihydrochloride (591 mg) describedin Reference Example 18 and triethylamine (930 μL) while washing withdehydrated methylene chloride (7.0 mL), followed by stirring at the sametemperature for 1 hour. This reaction mixture was filtered throughKiriyama filter paper. Subsequently, the residue was washed withmethanol and the filtrate was concentrated under reduced pressure. Theresulting residue was dissolved in methylene chloride and water, and theorganic layer extracted with methylene chloride was dried over magnesiumsulfate, followed by distilling off under reduced pressure. Theresulting residue was subjected to silica gel column chromatography(amino silica, chloroform/methanol=10/1) to afford 291.1 mg of the titlecompound as a colorless oil (yield 40%).

¹H NMR (400 MHz, CDCl₃) δ 1.45-1.85 (m, 4H), 2.29 (s, 6H), 2.60 (t,J=5.2 Hz, 2H), 2.81 (d, J=11.6 Hz, 1H), 2.97 (br d, J=11.6 Hz, 1H),3.28-3.34 (m, 1H), 3.92-4.07 (m, 3H), 4.90 (d, J=11.6 Hz, 1H), 5.05 (d,J=11.6 Hz, 1H), 7.35-7.48 (m, 5H);MS m/z 363 [M+H]⁺.

Step 2(2S,5R)—N-[2-(Dimethylamino)ethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.74-1.84 (m, 1H), 1.87-1.98 (m, 1H),2.03-2.12 (m, 1H), 2.15-2.24 (m, 1H), 2.36 (s, 6H), 2.67-2.74 (m, 2H),3.07 (br d, J=11.6 Hz, 1H), 3.12 (br d, J=11.6 Hz, 1H), 3.67-3.72 (m,1H), 3.83 (br d, J=6.4 Hz, 1H), 3.96-4.06 (m, 2H); MS m/z 273 [M+H]⁺.

Step 3(2S,5R)—N-[2-(Dimethylamino)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 18, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N-[2-(dimethylamino)ethoxyl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 130.7 mg of the title compound (2 steps, yield43%).

¹H NMR (400 MHz, D₂O) δ 1.68-1.84 (m, 2H), 1.86-2.04 (m, 2H), 2.80 (s,6H), 3.09-3.17 (m, 2H), 3.17-3.29 (m, 2H), 3.80-3.90 (m, 1H), 4.02-4.13(m, 3H); MS m/z 353 [M+H]⁺.

Example 66(2S,5R)—N-{[(2S)-2-Aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-066)

Step 1tert-Butyl{(2S)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg, 1.50 mmol) of Example 9 or 16 and (S)-tert-butyl(1-(aminooxy)propan-2-yl)carbamate (550 mg) described in ReferenceExample 19, 585.6 mg of the title compound was afforded (yield 87%).

¹H NMR (400 MHz, CDCl₃) δ 1.17 (d, J=6.4 Hz, 3H), 1.44 (s, 9H),1.55-1.70 (m, 1H), 1.90-2.10 (m, 2H), 2.26-2.34 (m, 1H), 2.80 (d, J=12.0Hz, 1H), 3.06 (br d, J=12.0 Hz, 1H), 3.27-3.34 (m, 1H), 3.64-3.74 (m,1H), 3.86-3.98 (m, 3H), 4.81 (br d, J=7.6 Hz, 1H), 4.90 (d, J=11.6 Hz,1H), 5.05 (d, J=11.6 Hz, 1H), 7.34-7.45 (m, 5H), 9.68 (br s, 1H); MS m/z449 [M+H]⁺.

Step 2 tert-Butyl{(2S)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.16 (d, J=6.4 Hz, 3H), 1.44 (s, 9H),1.74-1.84 (m, 1H), 1.86-1.98 (m, 1H), 2.03-2.12 (m, 1H), 2.21 (br dd,J=15.2, 6.8 Hz, 1H), 3.06 (d, J=12.0 Hz, 1H), 3.14 (br d, J=12.0 Hz,1H), 3.68-3.72 (m, 1H), 3.74-3.87 (m, 4H); MS m/z 359 [M+H]⁺.

Step 3(2S,5R)—N-{[(2S)-2-Aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{(2S)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamatewas afforded (quantitative). MS m/z 437 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 117.1 mg of the title compound (3 steps, yield26%).

¹H NMR (400 MHz, D₂O) δ 1.17 (d, J=6.8 Hz, 3H), 1.66-1.89 (m, 2H),1.91-2.08 (m, 2H), 3.02 (d, J=12.0 Hz, 1H), 3.18 (br d, J=12.0 Hz, 1H),3.47-3.58 (m, 1H), 3.82 (dd, J=11.8, 9.4 Hz, 1H), 3.92-4.02 (m, 2H),4.05-4.10 (m, 1H); MS m/z 339 [M+H]⁺.

Example 67(2S,5R)—N-{[(2R)-2-Aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-067)

Step 1 tert-Butyl{(2R)-1-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg, 1.50 mmol) of Example 9 or 16 and (R)-tert-butyl(1-(aminooxy)propan-2-yl)carbamate (569 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 15),625 mg of the title compound was afforded (yield 93%).

¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, J=6.4 Hz, 3H), 1.43 (s, 9H),1.53-1.70 (m, 1H), 1.90-2.06 (m, 2H), 2.28-2.36 (m, 1H), 2.79 (d, J=12.0Hz, 1H), 3.02 (br d, J=12.0 Hz, 1H), 3.28-3.33 (m, 1H), 3.56-3.68 (m,1H), 3.84 (dd, J=11.2, 3.6 Hz, 1H), 3.92-4.04 (m, 2H), 4.66 (br d, J=8.0Hz, 1H), 4.91 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.35-7.45 (m,5H), 9.94 (br s, 1H); MS m/z 449 [M+H]⁺.

Step 2 tert-butyl{(2R)-1-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.15 (d, J=6.4 Hz, 3H), 1.44 (s, 9H),1.73-1.84 (m, 1H), 1.86-2.00 (m, 1H), 2.01-2.12 (m, 1H), 2.19-2.29 (m,1H), 3.06 (d, J=11.6 Hz, 1H), 3.10-3.20 (m, 1H), 3.67-3.72 (m, 1H),3.73-3.92 (m, 4H); MS m/z 359 [M+H]⁺.

Step 3(2S,5R)—N-{[(2R)-2-Aminopropyl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{(2R)-1-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propan-2-yl}carbamatewas afforded (quantitative). MS m/z 437 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid and purified by octadecyl silica gel columnchromatography to afford 212.6 mg of the title compound (3 steps, yield45%).

¹H NMR (400 MHz, D₂O) δ 1.17 (d, J=6.8 Hz, 3H), 1.66-1.78 (m, 1H),1.78-1.88 (m, 1H), 1.90-2.06 (m, 2H), 3.02 (d, J=12.0 Hz, 1H), 3.18 (brd, J=12.0 Hz, 1H), 3.48-3.58 (m, 1H), 3.83 (dd, J=11.8, 9.0 Hz, 1H),3.94 (br d, J=7.2 Hz, 1H), 3.98 (dd, J=11.8, 3.4 Hz, 1H), 4.06-4.10 (m,1H); MS m/z 339 [M+H]⁺.

Example 68(2S,5R)—N-{[(2S)-1-Aminopropan-2-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl{(2S)-2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg,1.50 mmol) of Example 9 or 16 and (5)-tert-butyl(2-(aminooxy)propyl)carbamate (597 mg, prepared following proceduresanalogous to Reference Example 7 and Reference Example 15), 626.6 mg ofthe title compound was afforded (yield 93%).

¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6.4 Hz, 3H), 1.40-1.70 (m, 1H),1.44 (s, 9H), 1.92-2.08 (m, 2H), 2.27-2.36 (m, 1H), 2.77 (d, J=11.6 Hz,1H), 2.94-3.08 (m, 2H), 3.30-3.35 (m, 1H), 3.38-3.50 (m, 1H), 3.95-4.05(m, 2H), 4.91 (d, J=11.4 Hz, 1H), 5.05 (d, J=11.4 Hz, 1H), 5.48-5.60 (m,1H), 7.35-7.45 (m, 5H), 9.25 (br s, 1H); MS m/z 449 [M+H]⁺.

Step 2 tert-Butyl {(2S)-2-[({[(2S,5R)-6-hydroxy7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.20 (d, J=6.4 Hz, 3H), 1.44 (s, 9H),1.74-1.85 (m, 1H), 1.86-2.00 (m, 1H), 2.01-2.12 (m, 1H), 2.16-2.25 (m,1H), 3.06 (d, J=11.6 Hz, 1H), 3.10-3.18 (m, 2H), 3.23-3.38 (m, 1H),3.66-3.73 (m, 1H), 3.83-3.90 (m, 1H), 3.92-4.01 (m, 1H); MS m/z 359[M+H]⁺.

Step 3(2S,5R)—N-{[(2S)-1-Aminopropan-2-yl]oxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{(2S)-2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamatewas afforded (quantitative). MS m/z 437 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 175.0 mg of the title compound (3 steps, yield37%).

¹H NMR (400 MHz, D₂O) δ 1.19 (d, J=6.4 Hz, 3H), 1.67-1.88 (m, 2H),1.91-2.10 (m, 2H), 2.91-3.00 (m, 1H), 3.01-3.13 (m, 2H), 3.19 (br d,J=12.4 Hz, 1H), 3.95 (br d, J=7.2 Hz, 1H), 4.08 (br s, 1H), 4.11-4.20(m, 1H); MS m/z 339 [M+H]⁺.

Example 69(2S,5R)—N-(3-Aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-069)

Step 1 tert-Butyl{3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(3-(aminooxy)propyl)carbamate (730 mg) described in Reference Example20, the title compound 398.1 mg was afford (yield 63%).

¹H NMR (400 MHz, CDCl₃) δ 1.44 (s, 9H), 1.50-1.67 (m, 1H), 1.75-1.86 (m,2H), 1.88-2.07 (m, 2H), 2.28-2.37 (m, 2H), 2.77 (d, J=11.0 Hz, 1H), 3.01(br d, J=11.0 Hz, 1H), 3.20-3.38 (m, 3H), 3.89-4.04 (m, 3H), 4.90 (d,J=11.4 Hz, 1H), 5.05 (d, J=11.4 Hz, 1H), 5.17 (br s, 1H), 7.36-7.45 (m,5H), 9.21 (br s, 1H); MS m/z 449 [M+H]⁺.

Step 2 tert-Butyl{3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamate

Following a procedure analogous to Example 17, from the compound (392.8mg, 876 μmol) of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.43 (s, 9H), 1.73-1.99 (m, 4H), 2.01-2.12 (m,1H), 2.13-2.24 (m, 1H), 3.07 (d, J=11.6 Hz, 1H), 3.09-3.21 (m, 3H), 3.69(br s, 1H), 3.80-3.96 (m, 3H); MS m/z 359 [M+H]⁺.

Step 3(2S,5R)—N-(3-Aminopropoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl{3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]propyl}carbamatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 12H), 1.33-1.53 (m, 8H),1.47 (s, 9H), 1.55-1.96 (m, 12H), 2.14-2.23 (m, 1H), 2.31-2.41 (m, 1H),2.85 (br d, J=11.2 Hz, 1H), 3.15-3.42 (m, 11H), 3.88-4.07 (m, 3H), 4.35(br s, 1H), 5.27 (br s, 1H), 9.26 (br s, 1H); MS m/z 437 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 138.4 mg of the title compound (3 steps, yield47%).

¹H NMR (400 MHz, D₂O) δ 1.67-2.05 (m, 6H), 3.00-3.19 (m, 4H), 3.82-3.94(m, 3H), 4.05-4.10 (m, 1H); MS m/z 337 [M−H]⁻.

Example 70 Sodium(2S,5R)-2-(1,2-oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-7-oneStep 1(2S,5R)-6-Benzyloxy-2-(1,2-oxazolidin-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-7-one

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 550 mg, 2.00 mmol) of Example 9 or 16 and 1,2-oxazolidinehydrochloride (328.6 mg, commercially available), 588 mg of the titlecompound was afforded (yield 88.7%).

¹H NMR (400 MHz, CDCl₃) δ 1.26-2.34 (m, 6H), 2.95 (m, 1H), 3.33 (m, 2H),3.74 (m, 2H), 3.98-4.42 (m, 3H), 4.92 (m,1H), 5.03-5.06 (m, 1H),7.26-7.52 (m, 5H); MS m/z 332 [M+H]⁺.

Step 2 (2S,5R)-6-Hydroxy2-(1,2-oxazolidin-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-7-one

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 242 [M+H]⁺.

Step 3 Sodium(2S,5R)-2-(1,2-oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-7-one

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)-2-(1,2-oxazolidin-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-7-onewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 281.3 mg of the title compound (yield 46.9%).

¹H NMR (400 MHz, D₂O) δ 1.79-1.98 (m, 4H), 2.28-2.30 (m, 2H), 3.13-3.24(m, 2H), 3.61-4.33 (m, 6H); MS m/z 322 [M−Na+2H]⁺.

Example 71 Sodium(2S,5R)-2-(1,2-oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-7-oneStep 1(2S,5R)-6-benzyloxy-2-(1,2-oxazinan-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-7-one

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 552 mg, 2.00 mmol) of Example 9 or 16 and 1,2-oxazinane (261 mg),679 mg of the title compound was afforded (yield 98.3%).

¹H NMR (400 MHz, CDCl₃) δ 1.63-2.10 (m, 8H), 2.93-2.96 (br d, J=9.2 Hz,1H), 3.28-3.31 (d, J=11.6 Hz, 1H), 3.34 (s, 1H), 3.61 (br s, 1H),3.93-4.14 (m, 3H), 4.47 (br s, 1H), 4.89-4.92 (d, J=11.2 Hz, 1H),5.03-5.06 (d, J=11.6 Hz, 1H), 7.23-7.52 (m, 5H); MS m/z 346 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy2-(1,2-oxazinan-2-ylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-7-one

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 256 [M+H]⁺.

Step 3 Sodium(2S,5R)-2-(1,2-oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-7-one

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)-2-(1,2-oxazinan-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-7-onewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 297 mg of the title compound (yield 42.4%).

¹H NMR (400 MHz, D₂O) δ 1.64-1.97 (m, 8H), 2.99-3.16 (m, 1H), 3.21-3.24(d, J=12.0 Hz, 1H), 3.54-4.37 (m, 6H); MS m/z 336 [M−Na+2H]⁺.

Example 72 Sodium(2S,5R)—N-[2-(morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg, 1.50 mmol) of Example 9 or 16 andO-(2-morpholinoethyl)hydroxylamine (306 mg, Huhu Technology), 629.6 mgof the title compound was afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.60-1.73 (m, 1H), 1.85-2.06 (m, 2H), 2.33 (brdd, J=14.4, 7.6 Hz, 1H), 2.46-2.60 (m, 4H), 2.62-2.74 (m, 2H), 2.80 (d,J=11.8 Hz, 1H), 2.98 (br d, J=11.8 Hz, 1H), 3.28-3.34 (m, 1H), 3.70-3.81(m, 4H), 3.93 (br d, J=7.2 Hz, 1H), 3.97-4.11 (m, 2H), 4.90 (d, J=11.2Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.35-7.45 (m, 5H), 9.93 (br s, 1H); MSm/z 405 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N-[2-(morpholin-4-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 452.4 mg of the title compound wasafforded (yield 96%).

¹H NMR (400 MHz, CD₃OD) δ 1.77-1.85 (m, 1H), 1.86-1.98 (m, 1H),2.03-2.13 (m, 1H), 2.16-2.25 (m, 1H), 2.50-2.61 (m, 4H), 2.68 (t, J=5.4Hz, 2H), 3.05 (d, J=11.6 Hz, 1H), 3.12 (br d, J=11.6 Hz, 1H), 3.67-3.74(m, 5H), 3.84 (br d, J=7.2 Hz, 1H), 4.02-4.06 (m, 2H); MS m/z 315[M+H]⁺.

Step 3 Sodium(2S,5R)—N-[2-(morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 18, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N-[2-(morpholin-4-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 30.9 mg of the title compound (4 steps, yield21%).

¹H NMR (500 MHz, D₂O) δ 1.77-1.87 (m, 2H), 1.93-2.06 (m, 2H), 2.51-2.65(m, 4H), 2.67 (t, J=5.5 Hz, 2H), 3.16 (br d, J=11.8 Hz, 1H), 3.24 (d,J=11.8 Hz, 1H), 3.66-3.76 (m, 4H), 3.85 (br d, J=5.0 Hz, 1H), 3.95 (t,J=5.5 Hz, 2H), 4.13 (br s, 1H); MS m/z 395 [M−Na+2H]⁺.

Example 73(2S,5R)-7-Oxo-N-[2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl4-{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 552 mg, 2.00 mmol) of Example 9 or 16 and tert-butyl4-(2-(aminooxy)ethyl)piperazine-1-carboxylate (735 mg, preparedfollowing procedures analogous to Reference Example 7 and ReferenceExample 15), 476.5 mg of the title compound was afforded (yield 47.3%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.64-2.06 (m, 3H), 2.30-2.35 (m,1H), 2.58-2.66 (m, 4H), 2.68-2.69 (m, 2H), 2.77-2.80 (d, J=11.6 Hz, 1H),2.96-2.99 (d, J=11.6 Hz, 1H), 3.31 (br s, 1H), 3.79-3.82 (m, 4H),3.92-3.94 (d, J=8.0 Hz, 1H), 3.99-4.09 (m, 2H), 4.88-4.92 (d, J=11.2 Hz,1H), 5.04-5.07 (d, J=11.6 Hz, 1H), 7.34-7.42 (m, 5H); MS m/z 504 [M+H]⁺.

Step 2 tert-Butyl4-{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 414 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl4-{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}piperazine-1-carboxylatewas afforded (quantitative). MS m/z 492 [M−Bu₄N]⁻.

All amount of the tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 12.3 mg of the title compound (yield 3.3%).

¹H NMR (400 MHz, D₂O) δ 1.74 (m, 2H), 1.76 (m, 2H), 2.65-2.69 (m, 6H),2.96 (m, 4H), 2.98-2.99 (d, J=5.2 Hz, 1H), 3.17-3.20 (d, J=10.8 Hz, 1H),3.86-3.89 (m, 3H), 4.04 (br s, 1H); MS m/z 394 [M+H]⁺.

Example 74(2S,5R)-7-Oxo-N-[2-(1,4-diazepan-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-butyl4-{2-[({[(2S,5R)-6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepine-1-carboxylate

Following a procedure analogous to Example 17, from the carboxylic acid(6b, 548 mg, 1.98 mmol) of Example 9 or 16 and tert-butyl4-(2-(aminooxy)ethyl)-1,4-diazepine-1-carboxylate (921 mg, preparedfollowing procedures analogous to Reference Example 7 and ReferenceExample 15), 1.13 g of the title compound was afforded. MS m/z 518[M+H]⁺.

Step 2 tert-Butyl4-{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepine-1-carboxylate

Following a procedure analogous to Example 17, from all amount of thecompound of the above Step 1, 910 mg of the title compound was afforded.MS m/z 428 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[2-(1,4-diazepan-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of all the amount of the compound of the above Step 2 inmethylene chloride (20 mL) were added 2,6-lutidine (692 μl) and sulfurtrioxide-pyridine complex (945 mg), followed by agitating at roomtemperature overnight. After completion of the reaction, this reactionmixture was filtered, and the filtrate was concentrated to afford 1.67 gof pyridinium tert-butyl4-{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1,4-diazepine-1-carboxylate.MS m/z 506 [M−C₅H₅NH]⁻.

The above pyridinium salt (1.00 g, 1.19 mmol) was dissolved in methylenechloride (2.0 mL), and to which was added trifluoroacetic acid (2.0 mL)under ice-cooling and agitated at 0° C. for 30 minutes. The reactionsolution was concentrated under reduced pressure, and the resultingresidue was washed with diethyl ether, and adjusted pH with sodiumbicarbonate aqueous solution to pH 7, and then purified by octadecylsilica gel column chromatography (methanol/water=0/10-5/5). Afterlyophilisation, 111 mg of the title compound was afforded (4 steps,yield 23%).

¹H NMR (400 MHz, D₂O) δ 1.64-2.07 (m, 6H), 2.73-2.85 (m, 4H), 2.90-3.04(m, 3H), 3.13-3.28 (m, 5H), 3.90-3.98 (m, 3H), 4.05 -4.09 (m, 5H); MSm/z 408 [M+H]⁺.

Example 75(2S,5R)—N-[(2S)-Azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-075)

Step 1 tert-Butyl(2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (S)-tert-butyl2-((aminooxy)methyl)azetidine-1-carboxylate (578 mg) described inReference Example 21, 760.1 mg of the title compound was afforded (yield83%).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 1.56-1.70 (m, 1H), 1.88-2.07 (m,3H), 2.23-2.34 (m, 2H), 2.84 (d, J=11.6 Hz, 1H), 3.02 (d, J=11.6 Hz,1H), 3.28 (br s, 1H), 3.77-4.03 (m, 4H), 4.06-4.15 (m, 1H), 4.37-4.48(m, 1H), 4.89 (d, J=11.6 Hz, 1H), 5.04 (d, J=11.6 Hz, 1H), 7.34-7.44 (m,5H), 10.63 (br s, 1H); MS m/z 461 [M+H]⁺.

Step 2 tert-Butyl(2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate

Following a procedure analogous to Example 17, from the compound (699mg, 1.52 mmol) of the above Step 1, the title compound was afforded(quantitative). ¹H NMR (400 MHz, CD₃OD) δ 1.44 (s, 9H), 1.74-1.85 (m,1H), 1.86-1.99 (m, 1H), 2.02-2.14 (m, 1H), 2.16-2.40 (m, 3H), 3.06 (d,J=11.6 Hz, 1H), 3.10-3.17 (m, 1H), 3.67-3.74 (m, 1H), 3.75-3.93 (m, 3H),4.01 (dd, J=10.6, 10.6 Hz, 1H), 4.14 (dd, J=10.6, 10.6 Hz, 1H),4.37-4.47 (m, 1H); MS m/z 371 [M+H]⁺.

Step 3(2S,5R)—N-[(2S)-Azetidin-2-ylmethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all amount of thecompound of the above Step 2, tetrabutylammonium tert-butyl(2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.2 Hz, 12H), 1.30-2.10 (m, 19H),1.46 (s, 9H), 2.12 -2.39 (m, 3H), 2.89 (br d, J=12.0 Hz, 1H), 3.23-3.39(m, 9H), 3.76-3.93 (m, 3H), 3.95-4.06 (m, 1H), 4.08-4.18 (m, 1H), 4.33(br s, 1H), 4.37-4.50 (m, 1H); MS m/z 449 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography, 172.3 mg of the title compound was afforded (3 steps,yield 32%).

¹H NMR (500 MHz, D₂O) δ 1.71-1.83 (m, 1H), 1.84-1.97 (m, 1H), 1.98-2.16(m, 2H), 2.36-2.49 (m, 1H), 2.50-2.61 (m, 1H), 3.10 (d, J=12.0 Hz, 1H),3.22-3.30 (m, 1H), 3.92-4.12 (m, 5H), 4.25-4.36 (m, 1H), 4.68-4.77 (m,1H); MS m/z 351 [M+H]⁺.

Example 76(2S,5R)-7-Oxo-N-[(2S)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl(2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-tert-butyl2-((aminooxy)methyl)pyrrolidine-1-carboxylate (649 mg, preparedfollowing procedures analogous to Reference Example 7 and ReferenceExample 13), 477 mg of the title compound was afforded (yield 71%).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 1.62-1.77 (m, 1H), 1.70-2.07 (m,6H), 2.21-2.37 (m, 1H), 2.88 (br d, J=12.4 Hz, 1H), 2.98-3.10 (m, 1H),3.25-3.38 (m, 3H), 3.65-4.05 (m, 3H), 4.08-4.24 (m, 1H), 4.90 (d, J=11.6Hz, 1H), 5.05 (d, J=11.6 Hz, 1H), 7.32-7.46 (m, 5H), 10.22 (s, 1H); MSm/z 475 [M+H]⁺.

Step 2 tert-Butyl(2S)-2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl1pyrrolidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.46 (s, 9H), 1.72-2.27 (m, 8H), 2.99-3.18 (m,2H), 3.25-3.56 (m, 2H), 3.66-4.10 (m, 5H); MS m/z 385 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[(2S)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 26, from all the amount ofthe compound of the above Step 2, 385.6 mg of pyridinium tert-butyl(2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylatewas afforded (71%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.65-2.57 (m, 8H), 2.96-3.12 (m,1H), 3.25-3.44 (m, 4H), 3.68-4.18 (m, 3H), 4.25 (br s, 1H), 7.92-8.00(m, 2H), 8.45 (dd, J=7.6, 7.6 Hz, 1H), 8.98-9.07 (m, 1H), 10.61 (br s,1H); MS m/z 463 [M−C₅H₅NH]⁻.

All the amount of the above pyridinium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 58.1 mg of the title compound (3 steps, yield16%).

¹H NMR (400 MHz, D₂O) δ 1.78-2.12 (m, 8H), 3.04 (d, J=12.4 Hz, 1H), 3.18(br d, J=12.4 Hz, 1H), 3.24 (t, J=7.2 Hz, 2H), 3.83 (ddd, J=8.2, 8.2,3.4 Hz, 1H), 3.89-3.97 (m, 2H), 4.04-4.11 (m, 2H); MS m/z 365 [M+H]⁺.

Example 77(2S,5R)-7-Oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-077)

Step 1 tert-Butyl(2R)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl2-((aminooxy)methyl)pyrrolidine-1-carboxylate (796 mg) described inReference Example 22, 336 mg of the title compound was afforded (yield50%).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.52-1.72 (m, 1H), 1.80-2.09 (m,6H), 2.27-2.39 (m, 1H), 2.84 (br d, J=12.4 Hz, 1H), 2.96-3.08 (m, 1H),3.28-3.44 (m, 3H), 3.60-3.86 (m, 2H), 3.89-4.06 (m, 1H), 4.14-4.29 (m,1H), 4.90 (d, J=11.2 Hz, 1H), 5.06 (d, J=11.2 Hz, 1H), 7.32-7.47 (m,5H), 10.56 (s, 1H); MS m/z 475 [M+H]⁺.

Step 2 tert-Butyl(2R)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.46 (s, 9H), 1.73-2.27 (m, 8H), 3.06 (d,J=11.6 Hz, 1H), 3.09-3.18 (m, 1H), 3.24-3.40 (m, 2H), 3.67-3.71 (m, 1H),3.73-4.12 (m, 4H); MS m/z 385 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[(2R)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(2R)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 12H), 1.34-1.51 (m, 8H),1.46 (s, 9H), 1.55-1.78 (m, 10H), 1.80-2.01 (m, 4H), 2.11-2.23 (m, 1H),2.29-2.42 (m, 1H), 2.88 (br d, J=11.2 Hz, 1H), 3.21-3.43 (m, 10H),3.60-3.86 (m, 2H), 3.88-4.07 (m, 2H), 4.16-4.28 (m, 1H), 4.34 (br s,1H), 10.62 (br s, 1H); MS m/z 463 [M−Bu₄N+2H]⁺.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 77.4 mg of the title compound (3steps, yield30%).

¹H NMR (500 MHz, D₂O) δ 1.66-2.18 (m, 8H), 3.14 (d, J=12.8 Hz, 1H), 3.23(br d, J=12.8 Hz, 1H), 3.30 (t, J=7.3 Hz, 2H), 3.89 (ddd, J=8.2, 8.2,3.4 Hz, 1H), 3.92-4.01 (m, 2H), 4.09-4.18 (m, 2H); MS m/z 365 [M+H]⁺.

Example 78(2S,5R)-7-Oxo-N-[(2S)-piperidine-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-078)

Step 1 tert-Butyl(2S)-2-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 276 mg, 1.00 mmol) of Example 9 or 16 and (S)-tert-butyl2-((aminooxy)methyl)piperidine-1-carboxylate (300 mg) described inReference Example 23, 353.3 mg of the title compound was afforded (yield72%).

¹H NMR (400 MHz, CDCl₃) δ 1.30-1.75 (m, 7H), 1.46 (s, 9H), 1.90-2.10 (m,2H), 2.22-2.34 (m, 1H), 2.72-2.90 (m, 1H), 2.85 (d, J=11.2 Hz, 1H), 3.09(br d, J=11.2 Hz, 1H), 3.26-3.32 (m, 1H), 3.68-3.84 (m, 1H), 3.90-4.01(m, 2H), 4.06-4.15 (m, 1H), 4.44-4.58 (m, 1H), 4.90 (d, J=11.4 Hz, 1H),5.05 (d, J=11.4 Hz, 1H), 7.35-7.46 (m, 5H), 10.14 (br s, 1H); MS m/z 489[M+H]⁺.

Step 2 tert-Butyl(2S)-2-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.33-1.70 (m, 5H), 1.45 (s, 9H), 1.74-2.00 (m,3H), 2.03-2.12 (m, 1H), 2.17-2.26 (m, 1H), 2.82-2.93 (m, 1H), 3.06 (d,J=12.0 Hz, 1H), 3.14 (br d, J=12.0 Hz, 1H), 3.68-3.92 (m, 1H), 3.84 (brd, J=6.8 Hz, 1H), 3.92-4.08 (m, 3H), 4.43-4.51 (m, 1H); MS m/z 399[M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[(2S)-piperidine-2-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(2S)-2-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.2 Hz, 12H), 1.14-1.79 (m, 23H),1.45 (s, 9H), 1.84-2.00 (m, 1H), 2.12-2.23 (m, 1H), 2.24-2.38 (m, 1H),2.72-2.83 (m, 1H), 2.92 (br d, J=12.8 Hz, 1H), 3.21-3.34 (m, 8H),3.36-3.45 (m, 1H), 3.72-4.18 (m, 4H), 4.35 (br s, 1H), 4.45-4.56 (m,1H); MS m/z 477 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid and purified by octadecyl silica gel columnchromatography to afford 52.8 mg of the title compound (3 steps, yield19%).

¹H NMR (400 MHz, D₂O) δ 1.31-1.60 (m, 3H), 1.68-1.89 (m, 5H), 1.92-2.10(m, 2H), 2.82-2.91 (m, 1H), 3.05 (d, J=12.0 Hz, 1H), 3.18 (br d, J=12.0Hz, 1H), 3.26-3.40 (m, 2H), 3.87 (dd, J=11.8, 9.0 Hz, 1H), 3.94 (br d,J=7.2 Hz, 1H), 3.97 (dd, J=11.8, 3.4 Hz, 1H), 4.07-4.12 (m, 1H); MS m/z377 [M−H]⁻.

Example 79(2S,5R)—N-(Azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 413 mg, 1.50 mmol) of Example 9 or 16 and tert-butyl3-(aminooxy)azetidine-1-carboxylate (375 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 13),558 mg of the title compound was afforded (yield 84%).

[α]_(D) ²⁴−17.0° (c 0.30, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 1.43 (s,9H), 1.57-1.70 (m, 1H), 1.84-2.07 (m, 2H), 2.31 (br dd, J=14.6, 7.4 Hz,1H), 2.41 (d, J=11.4 Hz, 1H), 3.01 (br d, J=11.4 Hz, 1H), 3.29-3.34 (m,1H), 3.93-4.03 (m, 2H), 4.05-4.16 (m, 2H), 4.69-4.76 (m, 1H), 4.90 (d,J=11.6 Hz, 1H), 5.05 (d, J=11.6 Hz, 1H), 7.33-7.45 (m, 5H), 8.18 (br s,1H); MS m/z 447 [M+H]⁺.

Step 2 tert-Butyl3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylate

Following a procedure analogous to Example 17, from the compound (543mg, 1.22 mmol) of the above Step 1, 428 mg of the title compound wasafforded (99%).

¹H NMR (400 MHz, CD₃OD) δ 1.44 (s, 9H), 1.72-1.84 (m, 1H), 1.85-1.99 (m,1H), 2.00-2.11 (m, 1H), 2.15-2.24 (m, 1H), 3.00 (d, J=11.6 Hz, 1H), 3.11(br d, J=11.6 Hz, 1H), 3.69 (br s, 1H), 3.85 (br d, J=7.6 Hz, 1H),3.88-4.00 (m, 2H), 4.03-4.17 (m, 2H), 4.67-4.76 (m, 1H); MS m/z 357[M+H]⁺.

Step 3 (2S,5R)—N-(Azetidin-3-yloxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from the compound (424mg, 1.19 mmol) of the above Step 2, 739 mg of tetrabutylammoniumtert-butyl3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]azetidine-1-carboxylatewas afforded (yield 91%).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.4 Hz, 12H), 1.37-1.53 (m, 8H),1.44 (s, 9H), 1.57-1.78 (m, 9H), 1.83-1.96 (m, 1H), 2.14-2.23 (m, 1H),2.34 (br dd, J=15.0, 7.0 Hz, 1H), 2.79 (d, J=11.6 Hz, 1H), 3.23-3.40 (m,9H), 3.93 (br d, J=7.6 Hz, 1H), 3.95-4.15 (m, 4H), 4.33-4.38 (m, 1H),4.70-4.78 (m, 1H), 9.24 (br s, 1H); MS m/z 435 [M−Bu₄N]⁻.

The tetrabutylammonium salt (720 mg, 1.06 mmol) was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 144 mg of the title compound (yield 40%).

[α]_(D) ²⁵−69.2° (c 0.32, H₂O); ¹H NMR (400 MHz, D₂O) δ 1.67-1.78 (m,1H), 1.78-1.89 (m, 1H), 1.92-2.09 (m, 2H), 3.00 (d, J=12.2 Hz, 1H), 3.20(br d, J=12.2 Hz, 1H), 3.97 (br d, J=7.2 Hz, 1H), 4.04-4.14 (m, 3H),4.25-4.33 (m, 2H), 4.76-4.84 (m, 1H); MS m/z 337 [M+H]⁺.

Example 80(2S,5R)-7-Oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl(3R)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (R)-tert-butyl3-(aminooxy)pyrrolidine-1-carboxylate (606 mg) described in ReferenceExample 13, 904.6 mg of the title compound was afforded (yield 98.3%).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 1.61-1.68 (m, 1H), 1.83-2.09 (m,3H), 2.13-2.19 (m, 1H), 2.28-2.34 (m, 1H), 2.75 (d, J=11.6 Hz, 1H), 3.03(br d, J=11.6 Hz, 1H), 3.31-3.37 (m, 5H), 3.96 (d, J=6.8 Hz, 1H), 4.68(br s, 1H), 4.90 (d, J=11.6 Hz, 1H), 5.05 (d, J=11.6 Hz, 1H), 7.26-7.43(m, 5H), 9.06-9.20 (m, 1H); MS m/z 461 [M+H]⁺.

Step 2 tert-Butyl(3R)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate

Following a procedure analogous to Example 17, from the compound (805mg, 1.75 mmol) of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.46 (s, 9H), 1.75-2.12 (m, 4H), 2.15-2.28 (m,2H), 3.06 (d, J=11.6 Hz, 1H), 3.13 (br d, J=11.6 Hz, 1H), 3.25-3.50 (m,2H), 3.60 (br d, J=12.8 Hz, 1H), 3.70 (br s, 1H), 3.87 (br d, J=7.2 Hz,1H), 4.34-4.38 (m, 1H), 4.56-4.63 (m, 1H); MS m/z 371 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(3R)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylatewas afforded (quantitative). MS m/z 449 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 204.7 mg of the title compound (3 steps, yield33%).

¹H NMR (400 MHz, D₂O) δ 1.67-1.88 (m, 2H), 1.92-2.15 (m, 3H), 2.17-2.26(m, 1H), 3.02 (d, J=12.0 Hz, 1H), 3.20 (br d, J=12.0 Hz, 1H), 3.27-3.44(m, 3H), 3.48 (d, J=12.8 Hz, 1H), 3.96 (br d, J=7.2 Hz, 1H), 4.06-4.11(m, 1H), 4.69-4.74 (m, 1H); MS m/z 349 [M−H]⁻.

Example 81(2S,5R)-7-Oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-081)

Step 1 tert-Butyl(3S)-3-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (S)-tert-butyl3-(aminooxy)pyrrolidine-1-carboxylate (606 mg) described in ReferenceExample 24, 920.4 mg of the title compound was afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 1.61-1.68 (m, 1H), 1.89-2.09 (m,3H), 2.15-2.19 (m, 1H), 2.28-2.34 (m, 1H), 2.75 (d, J=11.6 Hz, 1H),2.95-3.06 (m, 1H), 3.31 (br s, 1H), 3.35-3.68 (m, 4H), 3.97 (d, J=7.6Hz, 1H), 4.60 (br d, J=23.2 Hz, 1H), 4.90 (d, J=11.6 Hz, 1H), 5.05 (d,J=11.6 Hz, 1H), 7.26-7.43 (m, 5H), 9.08 (br d, J=23.2 Hz, 1H); MS m/z461 [M+H]⁺.

Step 2 tert-Butyl(3S)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylate

Following a procedure analogous to Example 17, from the compound (869mg, 1.89 mmol) of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.47 (s, 9H), 1.75-2.12 (m, 4H), 2.13-2.25 (m,2H), 3.05 (d, J=12.0 Hz, 1H), 3.13 (br d, J=12.0 Hz, 1H), 3.25-3.50 (m,2H), 3.61 (br d, J=13.2 Hz, 1H), 3.70 (br s, 1H), 3.86 (br d, J=7.2 Hz,1H), 4.32-4.38 (m, 1H), 4.54-4.62 (m, 1H); MS m/z 371 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[(3S)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(3S)-3-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidine-1-carboxylatewas afforded (quantitative). MS m/z 449 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 170.7 mg of the title compound (3 steps, yield26%).

¹H NMR (400 MHz, D₂O) δ 1.71-1.92 (m, 2H), 1.95-2.18 (m, 3H), 2.21-2.30(m, 1H), 3.07 (d, J=12.2 Hz, 1H), 3.24 (br d, J=12.2 Hz, 1H), 3.31-3.45(m, 3H), 3.51 (d, J=13.6 Hz, 1H), 3.99 (br d, J=6.0 Hz, 1H), 4.10-4.14(m, 1H), 4.72-4.77 (m, 1H); MS m/z 349 [M−H]⁻.

Example 82(2S,5R)—N-(Azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(II-082)

Step 1 tert-Butyl3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 553 mg, 2.00 mmol) of Example 9 or 16 and tert-butyl3-((aminooxy)methyl)azetidine-1-carboxylate (564 mg) described inReference Example 25, 699.7 mg of the title compound was afforded (yield76%).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H), 1.54-1.70 (m, 1H), 1.87-2.06 (m,2H), 2.27-2.35 (m, 1H), 2.75 (d, J=11.6 Hz, 1H), 2.80-2.90 (m, 1H), 3.01(br d, J=11.6 Hz, 1H), 3.32 (br s, 1H), 3.68-3.76 (m, 2H), 3.94 (br d,J=7.6 Hz, 1H), 4.00-4.15 (m, 4H), 4.90 (d, J=11.8 Hz, 1H), 5.05 (d,J=11.8 Hz, 1H), 7.35-7.44 (m, 5H), 9.08 (br s, 1H); MS m/z 461 [M+H]⁺.

Step 2 tert-Butyl3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylate

Following a procedure analogous to Example 17, from the compound (642mg, 1.39 mmol) of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.43 (s, 9H), 1.74-1.85 (m, 1H), 1.86-1.97 (m,1H), 2.04-2.13 (m, 1H), 2.16-2.24 (m, 1H), 2.84-2.94 (m, 1H), 3.05 (d,J=11.6 Hz, 1H), 3.13 (br d, J=11.6 Hz, 1H), 3.68-3.82 (m, 3H), 3.83 (brd, J=6.8 Hz, 1H), 3.97-4.06 (m, 4H); MS m/z 371 [M+H]⁺.

Step 3 (2S,5R)—N-(Azetidin-3-ylmethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl3-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}azetidine-1-carboxylatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.2 Hz, 12H), 1.37-1.51 (m, 8H),1.46 (s, 9H), 1.54-1.75 (m, 9H), 1.82-1.97 (m, 1H), 2.13-2.25 (m, 1H),2.29-2.40 (m, 1H), 2.77-2.95 (m, 2H), 3.24-3.40 (m, 9H), 3.64-4.16 (m,7H), 4.36 (br s, 1H), 9.16 (br s, 1H); MS m/z 449 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 164.7 mg of the title compound (3 steps, yield34%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.89 (m, 2H), 1.92-2.06 (m, 2H), 3.06 (d,J=12.4 Hz, 1H), 3.10-3.22 (m, 2H), 3.90-4.00 (m, 5H), 4.07-4.14 (m, 3H);MS m/z 351 [M+H]⁺.

Example 83(2S,5R)-7-Oxo-N-[(3R)-piperidine-3-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl(3R)-3-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl3-((aminooxy)methyl)piperidine-1-carboxylate (527 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 13),333 mg of the title compound was afforded (yield 48%).

¹H NMR (400 MHz, CDCl₃) δ 1.15-2.10 (m, 8H), 1.45 (s, 9H), 2.25-2.40 (m,1H), 2.70-3.08 (m, 4H), 3.27-3.37 (m, 1H), 3.65-4.00 (m, 5H), 4.90 (d,J=11.2 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H), 7.34-7.46 (m, 5H), 9.22 (br s,1H); MS m/z 489 [M+H]⁺.

Step 2 tert-Butyl(3R)-3-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.24-1.37 (m, 1H), 1.40-1.56 (m, 1H), 1.45 (s,9H), 1.64-1.73 (m, 1H), 1.75-2.00 (m, 4H), 2.03-2.13 (m, 1H), 2.15-2.26(m, 1H), 2.65-2.95 (m, 2H), 3.06 (d, J=12.0 Hz, 1H), 3.13 (br d, J=12.0Hz, 1H), 3.67-3.91 (m, 5H), 4.01-4.08 (m, 1H); MS m/z 399 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[(3R)-piperidine-3-ylmethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from All the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl(3R)-3-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (dd, J=7.6, 6.8 Hz, 12H), 1.11-1.99 (m,23H), 1.46 (s, 9H), 2.12-2.24 (m, 1H), 2.30-2.42 (m, 1H), 2.67-2.96 (m,3H), 3.19-3.38 (m, 9H), 3.70-3.99 (m, 5H), 4.35 (br s, 1H), 9.16 (br s,1H); MS m/z 477 [M−Bu₄N]³¹ .

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 106 mg of the title compound (3 steps, yield41%).

¹H NMR (400 MHz, CDCl₃) δ 1.16-1.28 (m, 1H), 1.54-1.88 (m, 5H),1.92-2.16 (m, 3H), 2.72 (t, J=12.2 Hz, 1H), 2.81 (ddd, J=12.8, 12.8, 3.5Hz, 1H), 3.02 (d, J=12.0 Hz, 1H), 3.15-3.28 (m, 2H), 3.37-3.44 (m, 1H),3.70 (dd, J=10.3, 7.6 Hz, 1H), 3.79 (dd, J=10.3, 5.0 Hz, 1H), 3.88-3.94(m, 1H), 4.06-4.10 (m, 1H); MS m/z 377 [M−H]⁻.

Example 84(2S,5R)-7-Oxo-N-(piperidine-4-yloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl4-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 552 mg, 2.00 mmol) of Example 9 or 16 and tert-butyl4-(aminooxy)piperidine-1-carboxylate (1.08 g, prepared followingprocedures analogous to Reference Example 7 and Reference Example 13),688.5 mg of the title compound was afforded (yield 72.5%).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H), 1.58-1.66 (m, 5H), 1.85-2.02 (m,2H), 2.27 (m, 1H), 2.75-2.77 (br d, J=11.6 Hz, 1H), 2.99-3.02 (d, J=11.6Hz, 1H), 3.07-3.13 (m, 2H), 3.29 (s, 1H), 3.71-3.77 (m, 2H), 3.94-3.96(d, J=7.2 Hz, 1H), 3.98-4.08 (m,1H), 4.86-4.90 (d, J=11.2 Hz, 1H),5.01-5.05 (d, J=11.2 Hz, 1H), 7.34-7.41 (m, 5H), 9.02 (br s, 1H); MS m/z475 [M+H]⁺.

Step 2 tert-Butyl4-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 385 [M+H]+.

Step 3(2S,5R)-7-Oxo-N-(piperidine-4-yloxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl4-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylatewas afforded (quantitative). MS m/z 463 [M−Bu₄N]⁻.

All the amount of the tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 216.3 mg of the title compound (yield 40.9%).

¹H NMR (400 MHz, D₂O) δ 1.69-2.08 (m, 8H), 2.99-3.06 (m, 3H), 3.18-3.21(d, J=12.0 Hz, 1H), 3.26-3.31 (m, 2H), 3.96-3.97 (d, J=3.2 Hz, 1H),4.08-4.12 (m, 2H); MS m/z 365 [M+H]⁺.

Example 85(2S,5R)-7-Oxo-N-(piperidine-4-ylmethoxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl4-((aminooxy)methyl)piperidine-1-carboxylate (749 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 13),360.3 mg of the title compound was afforded (yield 52%).

¹H NMR (400 MHz, CDCl₃) δ 1.12-1.30 (m, 2H), 1.45 (s, 9H), 1.55-1.69 (m,1H), 1.70-1.79 (m, 2H), 1.80-2.07 (m, 3H), 2.27-2.38 (m, 1H), 2.60-2.80(m, 2H), 2.76 (d, J=11.8 Hz, 1H), 3.01 (br d, J=11.8 Hz, 1H), 3.31 (brs, 1H), 3.68-3.83 (m, 2H), 3.94 (br d, J=7.2 Hz, 1H), 4.02-4.20 (m, 2H),4.91 (d, J=11.4 Hz, 1H), 5.05 (d, J=11.4 Hz, 1H), 7.35-7.44 (m, 5H),9.04 (br s, 1H); MS m/z 489 [M+H]⁺.

Step 2 tert-Butyl4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CH₃OD) δ 1.11-1.23 (m, 2H), 1.45 (s, 9H), 1.74-1.97 (m,5H), 2.02-2.11 (m, 1H), 2.15-2.23 (m, 1H), 2.66-2.88 (m, 2H), 3.06 (d,J=11.2 Hz, 1H), 3.09-3.16 (m, 1H), 3.67-3.76 (m, 3H), 3.82 (br d, J=6.8Hz, 1H), 4.07 (br d, J=13.6 Hz, 2H); MS m/z 399 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-(piperidine-4-ylmethoxy)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, 504 mg of tetrabutylammoniumtert-butyl4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}piperidine-1-carboxylatewas afforded (yield 95%).

¹H NMR (400 MHz, CDCl₃) δ 1.01 (t, J=7.2 Hz, 12H), 1.17-1.82 (m, 21H),1.43 (s, 9H), 1.82-1.95 (m, 2H), 2.12-2.22 (m, 1H), 2.31-2.40 (m, 1H),2.63-2.78 (m, 2H), 2.84 (d, J=12.0 Hz, 1H), 3.16-3.38 (m, 9H), 3.70-3.86(m, 2H), 3.91 (br d, J=7.6 Hz, 1H), 4.00-4.19 (m, 2H), 4.34 (br s, 1H),9.15 (br s, 1H); MS m/z 477 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 103 mg of the title compound (3 steps, yield37%).

¹H NMR (400 MHz, D₂O) δ 1.30-1.46 (m, 2H), 1.68-2.11 (m, 7H), 2.85-2.95(m, 2H), 3.03 (d, J=12.0 Hz, 1H), 3.19 (br d, J=12.0 Hz, 1H), 3.34 (brd, J=12.0 Hz, 2H), 3.73 (d, J=6.0 Hz, 2H), 3.93 (d, J=7.2 Hz, 1H),4.06-4.14 (m, 1H); MS m/z 377 [M−H]⁻.

Example 86 Sodium(2S,5R)—N-[2-(1H-Imidazol-1-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-benzyloxy-N-[2-(1H-Imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 552 mg, 2.00 mmol) of Example 9 or 16 andO-(2-(1H-Imidazol-1-yl)ethyl)hydroxylamine (386 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 13),770 mg of the title compound was afforded (quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.70-1.71 (m, 1H), 1.81-1.96 (m, 2H),2.09-2.14 (m, 1H), 2.90-2.93 (br d, J=11.6 Hz, 1H), 3.14 (m, 1H),3.80-3.85 (m, 2H), 4.12 (m, 1H), 4.22-4.35 (m,2H), 4.85-4.96 (dd, J=11.2Hz, 2H), 7.05 (s, 1H), 7.22-7.41 (m, 6H), 8.05 (s,1H); MS m/z 386[M+H]⁺.

Step 2 (2S,5R)-6-Hydroxy-N-[2-(1H-Imidazol-1-yl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 296 [M+H]⁺.

Step 3 Sodium(2S,5R)—N-[2-(1H-Imidazol-1-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 18, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N-[2-(1H-Imidazol-1-yl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford the title compound 63.6 mg (yield 8.00%).

¹H NMR (400 MHz, D₂O) δ 1.66-1.85 (m, 2H), 1.97-2.09 (m, 2H), 2.94-2.97(d, J=12.0 Hz, 1H), 3.14-3.17 (d, J=11.6 Hz, 1H), 3.87-3.89 (d, J=7.2Hz, 1H), 4.07 (s, 1H), 4.13-4.15 (m, 2H),4.23-4.26 (m, 2H), 7.00 (s,1H), 7.19 (s, 1H), 7.86 (s, 1H); MS m/z 376 [M−Na+2H]⁺.

Example 87 Sodium(2S,5R)-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 690 mg, 2.50 mmol) of Example 9 or 16 andO-(2-(1H-pyrrol-1-yl)ethyl)hydroxylamine (450.5 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 15),506 mg of the title compound was afforded (yield 52.6%).

¹H NMR (400 MHz, CDCl₃) δ 1.60-1.65 (m, 1H), 1.87-2.03 (m, 2H),2.26-2.31 (m, 1H), 2.66-2.69 (d, J=11.6 Hz, 1H), 2.93-2.96 (br d, J=11.6Hz, 1H), 3.29 (br s, 1H), 3.88-3.90 (d, J=7.6 Hz, 1H), 4.09-4.23 (m,4H), 4.87-4.90 (d, J=11.6 Hz, 1H), 5.02-5.05 (d, J=11.6 Hz, 1H), 6.17(s, 2H), 6.71 (s, 2H), 7.33-7.43 (m, 5H); MS m/z 385 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of Example 17, the title compound was afforded(quantitative). MS m/z 295 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)-7-oxo-N-[2-(1H-pyrrol-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 153 mg of the title compound (yield 29.4%).

¹H NMR (400 MHz, D₂O) δ 1.64-1.83 (m, 2H), 1.91-2.08 (m, 2H), 2.91-2.94(d, J=12.0 Hz, 1H), 3.13-3.16 (br d, J=12.0 Hz, 1H), 3.87-3.89 (d,J=11.6 Hz, 1H), 4.05-4.09 (m, 5H), 6.17 (s, 2H), 6.74 (s, 2H); MS m/z375 [M−Na+2H]⁺.

Example 88 Disodium1-{2-([({[(2S,5R)-7-oxo-6-(sulfonateoxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}-1H-Imidazol-2-sulfonate

A fraction resulting from purification by octadecyl silica gel columnchromatography in Example 86, Step 3 gave 71.6 mg of the title compound(yield 7.16%).

¹H NMR (400 MHz, D₂O) δ 1.66-1.73 (m, 1H), 1.76-1.86 (m, 1H), 1.92-2.08(m, 2H), 2.96-2.99 (d, J=12.0 Hz, 1H), 3.17-3.20 (d, J=12.4 Hz, 1H),3.92-3.94 (d, J=8.0 Hz, 1H), 4.07-4.08 (d, J=3.2 Hz, 1H), 4.22-4.24 (m,2H), 4.41-4.44 (m, 2H),7.53 (s,1H), 7.61 (s, 1H); MS m/z 456[M−2Na+3H]⁺.

Example 89 Sodium(2S,5R)—N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 428 mg, 1.55 mmol) of Example 9 or 16 and2-(aminooxy)-N,N-dimethylacetamide (244 mg, Huhu Technology), 269.2 mgof the title compound was afforded (yield 46%).

¹H NMR (400 MHz, CDCl₃) δ 1.50-1.70 (m, 1H), 1.87-2.10 (m, 2H),2.24-2.37 (m, 1H), 2.78 (d, J=12.0 Hz, 1H), 2.91 (s, 3H), 2.97 (s, 3H),3.03 (br d, J=12.0 Hz, 1H), 3.26-3.32 (m, 1H), 3.90-3.96 (m, 1H),4.50-4.67 (m, 2H), 4.90 (d, J=11.4 Hz, 1H), 5.04 (d, J=11.4 Hz, 1H),7.35-7.45 (m, 5H), 10.04 (br s, 1H); MS m/z 377 [M+H]⁺.

Step 2(2S,5R)—N-[2-(Dimethylamino)-2-oxoethoxy]-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.73-1.84 (m, 1H), 1.85-1.99 (m, 1H),2.02-2.12 (m, 1H), 2.16-2.26 (m, 1H), 2.95 (s, 3H), 3.02-3.15 (m, 2H),3.05 (s, 3H), 3.67-3.73 (m, 1H), 3.85 (br d, J=7.2 Hz, 1H), 4.57-4.68(m, 2H); MS m/z 287 [M+H]⁺.

Step 3 Sodium(2S,5R)—N-[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 18, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N[2-(dimethylamino)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified with octadecyl silica gel columnchromatography to afford 180.0 mg of the title compound (2 steps, yield65%).

¹H NMR (500 MHz, D₂O) δ 1.72-1.85 (m, 2H), 1.89-2.20 (m, 2H), 2.86 (s,3H), 2.99 (s, 3H), 3.11 (br d, J=11.8 Hz, 1H), 3.28 (br d, J=11.8 Hz,1H), 3.76-3.81 (m, 1H), 4.08-4.12 (m, 1H), 4.49 (s, 2H); MS m/z 367[M−Na+2H]⁺.

Example 90(2S,5R)-7-Oxo-N-[2-oxo-2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 552 mg, 2.00 mmol) of Example 9 or 16 and tert-butyl4-(2-(aminooxy)acetyl)piperazine-1-carboxylate (686.2 mg, preparedfollowing procedures analogous to Reference Example 14 and ReferenceExample 15), 499.8 mg of the title compound was afforded (yield 48.3%).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H), 1.67 (m, 1H), 1.90-2.04 (m, 2H),2.26-2.31 (m, 1H), 2.75-2.78 (d, J=11.6 Hz, 1H), 3.01-3.04 (d, J=11.6Hz, 1H), 3.33 (m, 3H), 3.45 (m, 4H), 3.58 (m, 2H), 3.92-3.94 (d, J=11.2Hz, 1H), 4.53-4.56 (d, J=14.4 Hz, 1H), 4.60-4.63 (d, J=14.4 Hz, 1H),4.88-4.92 (d, J=11.6 Hz, 1H), 5.02-5.07 (d, J=11.6 Hz, 1H), 7.26-7.43(m, 5H); MS m/z 518 [M+H]⁺.

Step 2 tert-Butyl4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 428 [M+H]⁺.

Step 3(2S,5R)-7-Oxo-N-[2-oxo-2-(piperazin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}piperazine-1-carboxylatewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.00 (m, 12H), 1.40 (m, 8H), 1.43 (s, 9H),1.62 (m, 8H), 1.84-1.94 (m, 1H), 2.08 (m, 1H), 2.16-2.20 (m, 1H),2.29-2.34 (m, 1H), 2.81-2.84 (d, J=12.0 Hz, 1H), 3.35-3.37 (m, 3H), 3.45(m, 4H), 3.54 (m, 2H), 3.89-3.92 (d, J=12.4 Hz, 1H),4.09-4.14 (m, 8H),4.31 (br s, 1H), 4.51-4.59 (d, J=14.4 Hz, 1H), 4.61-4.65 (d, J=14.4 Hz,1H); MS m/z 508 [M−Bu₄N+H]⁺.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid and purified by octadecyl silica gel columnchromatography to afford 149.8 mg of the title compound (yield 38.1%).

¹H NMR (400 MHz, D₂O) δ 1.17-1.89 (m, 2H), 1.96-2.12 (m, 2H), 3.05-3.08(d, J=12.4 Hz, 1H), 3.19-3.26 (dt, J=5.2, 16.8 Hz, 4H), 3.22 (m, 1H),3.68-3.75 (dt, J=5.2, 16.8 Hz, 4H), 3.94-3.96 (d, J=5.6 Hz, 1H),4.11-4.12 (br s, 1H), 4.61-4.68 (m, 2H); MS m/z 408 [M+H]⁺.

Example 91

Sodium(2S,5R)—N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Step 1(2S,5R)-6-Benzyloxy-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 690 mg, 2.50 mmol) of Example 9 or 16 and2-(aminooxy)-1-morpholinoethanone (641 mg, prepared following proceduresanalogous to Reference Example 14 and Reference Example 15), 941.9 mg ofthe title compound was afforded (yield 90.0%).

¹H NMR (400 MHz, CDCl₃) δ 1.61-1.66 (m, 1H), 1.91-2.04 (m, 2H),2.21-2.31 (m, 1H), 2.77-2.79 (d, J=11.6 Hz, 1H), 2.96-2.97 (d, J=4.4 Hz,1H), 3.01-3.04 (br d, J=11.2 Hz, 1H), 3.29-3.38 (m, 4H), 3.57-3.70 (m4H), 3.92-3.94 (d, J=7.2 Hz, 1H), 4.52-4.66 (dd, J=11.6,14.4 Hz, 2H),4.87-4.91 (d, J=11.6 Hz, 1H), 5.02-5.05 (d, J=11.6 Hz, 1H), 7.36-7.47(m, 5H); MS m/z 419 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 329 [M+H]⁺.

Step 3 Sodium(2S,5R)—N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N-[2-(morpholin-4-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 152 mg of the title compound (yield 15.7%).

¹H NMR (400 MHz, D₂O) δ 1.67-1.85 (m, 2H), 1.92-2.04 (m, 2H), 3.00-3.03(d, J=12.0 Hz, 1H), 3.15-3.18 (d, J=12.0 Hz, 1H), 3.37-3.47 (m, 4H),3.60-3.62 (m, 4H), 3.90-3.92 (d, J=6.4 Hz, 1H), 4.6 (br s, 1H),4.62-4.68 (m, 2H); MS m/z 409 [M−Na+2H]⁺.

Example 92(2S,5R)—N-[2-(1,4-Diazepan-1-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1 tert-Butyl4-{[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepine-1-carboxylate

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 690 mg, 2.50 mmol) of Example 9 or 16 and tert-butyl4-(2-(aminooxy)acetyl)-1,4-diazepine-1-carboxylate (1.298 g) describedin Reference Example 15, 517.6 mg of the title compound was afforded(yield 38.9%).

¹H NMR (400 MHz, CDCl₃) δ 1.44 (s, 9H), 1.58 (m, 1H), 1.83-1.96 (m, 3H),2.27 (m, 1H), 2.75 (m, 1H), 2.99 (m, 1H), 3.30-3.80 (m, 9H), 3.90 (br s,1H), 4.58 (m, 2H), 4.88 (m, 1H), 5.03 (m, 1H), 7.24-7.37 (m, 5H); MS m/z532 [M+H]⁺.

Step 2 tert-Butyl4-{[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepine-1-carboxylate

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 442 [M+H]⁺.

Step 3(2S,5R)—N-[2-(1,4-Diazepan-1-yl)-2-oxoethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 2, tetrabutylammonium tert-butyl4-{[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetyl}-1,4-diazepine-1-carboxylatewas afforded (quantitative). MS m/z 520 [M−Bu₄N]⁻.

The above tetrabutylammonium salt (742.4 mg, 0.973 mmol) was deprotectedwith trifluoroacetic acid, and then purified by octadecyl silica gelcolumn chromatography to afford 153.1 mg of the title compound (yield37.3%).

¹H NMR (400 MHz, D₂O) δ 1.71-1.89 (m, 2H), 1.97-2.16 (m, 4H), 3.06-3.10(d, J=12.0 Hz, 1H), 3.19-3.22 (d, J=12.4 Hz, 1H), 3.25-3.29 (m, 3H),3.36-3.39 (m, 2H), 3.50-3.60 (m, 2H), 3.73-3.75 (m, 2H), 3.94-3.95 (d,J=7.2 Hz, 1H), 4.11 (s, 1H), 4.62-4.69 (m, 2H); MS m/z 422 [M+H]⁺.

Example 93 Sodium(2S,5R)-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 27, from the carboxylic acid(6b, 550 mg, 2.00 mmol) of Example 9 or 16 and1-(2-(aminooxy)ethyl)pyrrolidin-2-one (518.4 mg), 699.5 mg of the titlecompound was afforded (yield 86.9%).

¹H NMR (400 MHz, CDCl₃) δ 1.60-1.66 (m, 1H), 1.92-2.11 (m, 4H),2.26-2.31 (m, 1H), 2.40-2.44 (m, 2H), 2.78-2.81 (br d, J=12.0 Hz, 1H),3.06-3.09 (d, J=11.6 Hz, 1H), 3.27 (br s, 1H), 3.33-3.38 (m, 1H),3.44-3.54 (m, 2H), 3.68-3.74 (m, 1H), 3.94-4.14 (m, 3H), 4.87-4.90 (d,J=11.2 Hz, 1H), 5.02-5.04 (d, J=11.2 Hz, 1H), 7.26-7.42 (m, 5H), 10.10(br s, 1H); MS m/z 403 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative). MS m/z 313 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-N-[2-(2-oxopyrrolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 22, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)-7-oxo-N42-(2-oxopyrrolidin-1-yl)ethoxyl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 460.6 mg of the title compound (yield 64.2%).

¹H NMR (400 MHz, D₂O) δ 1.67-1.73 (m, 1H), 1.79-1.87 (m, 1H), 1.90-2.06(m, 4H), 2.30-2.34 (t, J=8.4 Hz, 1H), 3.01-3.08 (d, J=12.4 Hz, 1H),3.19-3.22 (d, J=12.0 Hz, 1H), 3.38-3.50 (m, 4H), 3.93-3.99 (m, 3H), 4.09(br s, 1H); MS m/z 393 [M−Na+2H]⁺.

Example 94 Sodium(2S,5R)-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 390 mg, 1.41 mmol) of Example 9 or 16 and1-(2-(aminooxy)ethyl)imidazolidin-2-one (512 mg, prepared followingprocedures analogous to Reference Example 7 and Reference Example 15),347 mg of the title compound was afforded (yield 61%).

¹H NMR (400 MHz, CDCl₃) δ 1.50-1.68 (m, 1H), 1.91-2.06 (m, 2H),2.24-2.35 (m, 1H), 2.80 (d, J=12.0 Hz, 1H), 3.06 (br d, J=12.0 Hz, 1H),3.21-3.39 (m, 2H), 3.40-3.68 (m, 5H), 3.92-4.06 (m, 3H), 4.32 (br s,1H), 4.89 (d, J=11.6 Hz, 1H), 5.04 (d, J=11.6 Hz, 1H), 7.33-7.44 (m,5H), 10.10 (br s, 1H); MS m/z 404 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, all the amount of thecompound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.74-1.84 (m, 1H), 1.87-2.13 (m, 2H),2.16-2.27 (m, 1H), 3.04 (d, J=11.6 Hz, 1H), 3.11-3.18 (m, 1H), 3.27-3.49(m, 4H), 3.58-3.66 (m, 2H), 3.67-3.73 (m, 1H), 3.85 (br d, J=7.6 Hz,1H), 3.92-4.05 (m, 2H); MS m/z 314 [M+H]⁺.

Step 3 Sodium(2S,5R)-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of all the amount of the compound of the above Step 2 inmethylene chloride (8.6 mL) were added 2,6-lutidine (300 μl)and sulfurtrioxide-pyridine complex (410 mg), followed by agitating at roomtemperature overnight. To the reaction solution was added methylenechloride, followed by filtration and concentration under reducedpressure. To the resulting 486.7 mg of pyridinium(2S,5R)-7-oxo-N-[2-(2-oxoimidazolidin-1-yl)ethoxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas added sodium bicarbonate aqueous solution, followed bylyophilisation. Thereby, the crude product was afforded. The resultingcrude product was purified by octadecyl silica gel column chromatographyto afford 36.8 mg of the title compound (2 steps, yield 10%).

¹H NMR (400 MHz, D₂O) δ 1.59-2.08 (m, 4H), 3.02 (d, J=12.6 Hz, 1H), 3.18(br d, J=12.6 Hz, 1H), 3.27-3.49 (m, 4H), 3.59-3.67 (m, 2H), 3.90-3.98(m, 3H), 4.05-4.10 (m, 1H); MS m/z 394 [M−Na+2H]⁺.

Example 95 Sodium(2S,5R)—N-(2-hydroxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-7-oxo-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 553 mg, 2.00 mmol) of Example 9 or 16 andO-(2-((triisopropylsilyl)oxy)ethyl)hydroxylamine (630 mg, preparedfollowing a procedure analogous to Reference Example 15 from thecompound of Reference Example 12), 695.0 mg of the title compound wasafforded (yield 71%).

¹H NMR (400 MHz, CDCl₃) δ 1.00-1.20 (m, 21H), 1.57-1.70 (m, 1H),1.88-2.10 (m, 2H), 2.28-2.37 (m, 1H), 2.78 (d, J=11.6 Hz, 1H), 2.98 (brd, J=11.6 Hz, 1H), 3.31 (br s, 1H), 3.87-4.08 (m, 5H), 4.90 (d, J=11.4Hz, 1H), 5.05 (d, J=11.4 Hz, 1H), 7.35-7.45 (m, 5H), 9.38 (br s, 1H); MSm/z 492 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-7-oxo-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 530.7 mg of the title compound wasafforded (yield 94%).

¹H NMR (400 MHz, CD₃OD) δ 1.00-1.20 (m, 21H), 1.74-1.85 (m, 1H),1.86-1.99 (m, 1H), 2.01-2.13 (m, 1H), 2.15-2.25 (m, 1H), 3.06 (d, J=11.6Hz, 1H), 3.12 (br d, J=11.6 Hz, 1H), 3.69 (br s, 1H), 3.82 (br d, J=7.2Hz, 1H), 3.90-4.01 (m, 4H); MS m/z 402 [M+H]⁺.

Step 3 Sodium(2S,5R)—N-(2-hydroxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 59, from all the amount ofthe compound of the above Step 2, tetrabutylammonium(2S,5R)-7-oxo-6-(sulfooxy)-N-(2-triisopropylsilyloxyethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 0.87-1.19 (m, 33H), 1.36-1.98 (m, 18H),2.13-2.23 (m, 1H), 2.31-2.42 (m, 1H) 2.85 (br d, J=11.6 Hz, 1H),3.21-3.38 (m, 9H), 3.83-4.17 (m, 5H), 4.35 (br s, 1H), 9.37 (br s, 1H);MS m/z 480 [M−Bu₄N]⁻.

All the amount of the above tetrabutylammonium salt was deprotected withtrifluoroacetic acid, and then purified by octadecyl silica gel columnchromatography to afford 140.2 mg of the title compound (3 steps, yield29%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.88 (m, 2H), 1.91-2.08 (m, 2H), 3.04 (d,J=12.0 Hz, 1H), 3.18 (br d, J=12.0 Hz, 1H), 3.63-3.69 (m, 2H), 3.85-3.96(m, 3H), 4.05-4.09 (m, 1H); MS m/z 324 [M−Na]⁻.

Example 96 Sodium(2S,5R)—N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-N-(2-methoxyethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg, 1.50 mmol) of Example 9 or 16 andO-(2-methoxyethyl)hydroxylamine (190 mg, Huhu Technology), 386.7 mg ofthe title compound was afforded (yield 74%).

¹H NMR (400 MHz, CDCl₃) δ 1.57-1.72 (m, 1H), 1.88-2.10 (m, 2H),2.29-2.37 (m, 1H), 2.78 (d, J=11.8 Hz, 1H), 2.99 (br d, J=11.8 Hz, 1H),3.30 (br s, 1H), 3.39 (s, 3H), 3.63 (t, J=4.4 Hz, 2H), 3.95 (br d, J=7.6Hz, 1H), 4.01-4.15 (m, 2H), 4.90 (d, J=11.4 Hz, 1H), 5.05 (d, J=11.4 Hz,1H), 7.35-7.45 (m, 5H), 9.32 (br s, 1H); MS m/z 350 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N-(2-methoxyethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, 272.4 mg of the title compound wasafforded (yield 95%).

¹H NMR (400 MHz, CH₃OD) δ 1.74-1.85 (m, 1H), 1.86-1.98 (m, 1H),2.02-2.12 (m, 1H), 2.16-2.25 (m, 1H), 3.08 (d, J=11.6 Hz, 1H), 3.12 (brd, J=11.6 Hz, 1H), 3.37 (s, 3H), 3.61-3.65 (m, 2H), 3.67-3.72 (m, 1H),3.82 (br d, J=8.4 Hz, 1H), 3.99-4.03 (m, 2H); MS m/z 260 [M+H]⁺.

Step 3 Sodium(2S,5R)—N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 18, from all the amount ofthe compound of the above Step 2, pyridinium(2S,5R)—N-(2-methoxyethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas afforded, and neutralized with saturated sodium bicarbonate aqueoussolution, and then purified by octadecyl silica gel columnchromatography to afford 247.4 mg of the title compound (2 steps, yield62%).

¹H NMR (500 MHz, D₂O) δ 1.69-1.78 (m, 1H), 1.78-1.88 (m, 1H), 1.93-2.01(m, 1H), 2.01-2.09 (m, 1H), 3.06 (d, J=12.3 Hz, 1H), 3.20 (br d, J=12.3Hz, 1H), 3.28 (s, 3H), 3.57-3.62 (m, 2H), 3.94 (br d, J=6.5 Hz, 1H),3.94-3.99 (m, 2H), 4.08-4.13 (m, 1H); MS m/z 340 [M−Na+2H]⁺.

Example 97 Sodium(2S,5R)—N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamideStep 1(2S,5R)-6-Benzyloxy-N-[2-(methylsulfonyl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 45, from the carboxylic acid(6b, 414 mg, 1.50 mmol) of Example 9 or 16 andO-(2-(methylsulfonyl)ethyl)hydroxylamine (279 mg, Huhu Technology), 293mg of the title compound was afforded (yield 49%).

¹H NMR (400 MHz, CDCl₃) δ 1.44-1.70 (m, 1H), 1.90-2.10 (m, 2H),2.24-2.36 (m, 1H), 2.74 (d, J=12.0 Hz, 1H), 3.04 (br d, J=12.0 Hz, 1H),3.12 (s, 3H), 3.31-3.39 (m, 3H), 3.96 (br d, J=7.6 Hz, 1H), 4.38 (br t,J=5.4 Hz, 2H), 4.91 (d, J=11.4 Hz, 1H), 5.05 (d, J=11.4 Hz, 1H),7.36-7.45 (m, 5H), 9.31 (br s, 1H); MS m/z 398 [M+H]⁺.

Step 2(2S,5R)-6-Hydroxy-N-[2-(methylsulfonyl)ethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

Following a procedure analogous to Example 17, from all the amount ofthe compound of the above Step 1, the title compound was afforded(quantitative).

¹H NMR (400 MHz, CD₃OD) δ 1.77-1.86 (m, 1H), 1.87-1.99 (m, 1H),2.03-2.13 (m, 1H), 2.17-2.26 (m, 1H), 3.04 (d, J=12.0 Hz, 1H), 3.07-3.18(m, 4H), 3.46 (t, J=5.6 Hz, 2H), 3.68-3.74 (m, 1H), 3.86 (br d, J=6.4Hz, 1H), 4.30 (t, J=5.6 Hz, 2H); MS m/z 308 [M+H]⁺.

Step 3 Sodium(2S,5R)—N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

To a solution of a total amount of the compound of the above Step 2 inmethylene chloride (7.4 mL) were added 2,6-lutidine (257 μl) and sulfurtrioxide-pyridine complex (352 mg), followed by agitating at roomtemperature overnight. The resulting pyridinium(2S,5R)—N-[2-(methylsulfonyl)ethoxy]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewas neutralized by adding saturated sodium bicarbonate aqueous solution.The organic solvent was distilled off under reduced pressure, followedby lyophilization, thereby the crude product was afforded. The resultingcrude product was purified by octadecyl silica gel column chromatographyto afford 51.1 mg of the title compound (2 steps, yield 17%).

¹H NMR (400 MHz, D₂O) δ 1.65-1.86 (m, 2H), 1.90-2.06 (m, 2H), 3.00-3.10(m, 1H), 3.05 (s, 3H), 3.06 (d, J=12.0 Hz, 1H), 3.15 (br d, J=12.0 Hz,1H), 3.49 (br t, J=5.6 Hz, 2H), 3.86-3.93 (m, 1H), 4.05-4.09 (m, 1H),4.22 (br t, J=5.6 Hz, 1H); MS m/z 388 [M−Na+2H]⁺.

Example 98(2S,5R)-5-(Benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylicacid (IV-a2)

A solution of (2S,5R)-tert-Butyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(1.50 g, 3.73 mmol) in methylene chloride (5.0 mL) was ice-cooled, andtrifluoroacetic acid (5.0 mL) was added, and reacted at the sametemperature for 30 min and then at room temperature for 2 h. Thereaction mixture was concentrated under reduced pressure, then water and6.5% sodium bicarbonate aqueous solution was added to the residue. AfterpH was adjusted to ca. pH 8, aqueous layer was washed with ethylacetate. To this aqueous layer was added 5% potassium hydrogen sulfateaqueous solution. After pH was adjusted to ca. pH 5.6, the aqueous layerwas extracted with ethyl acetate. After the organic layer was washedwith saturated brine, dehydrated over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure to afford 0.913 gof the title compound (yield 71%).

¹H NMR (400 MHz, CDCl₃) δ observed as a mixture of 2 rotamers (approx.6:4). 1.68-1.76 (m, 2H), 2.05-2.08 (m, 2H), 3.14 (d, J=14.4 Hz, 0.4H),3.27 (m, 1H), 3.48 (m, 0.6H), 4.15 (m, 1H), 4.58-4.75 (m, 3H), 5.20 (m,1H), 4.30-4.38 (m, 5H); MS m/z 347 [M+H]⁺.

Example 99(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (IV-a3)

(2S,5R)-5-(Benzyloxyamino)piperidine-2-carboxylic acid, dihydrochloride(2.00 g, 6.19 mmol) described in Example 11 was added to 1,4-dioxane (10mL) and water (15 mL), followed by addition of 5M sodium hydroxideaqueous solution (3.7 mL), and stirred under ice cooling. Furtherpotassium carbonate (854 mg) and di-tert-butoxycarbonyl dicarbonate(1.69 g) were added to the mixture, and a temperature was elevated toroom temperature, followed by stirring overnight. The resulting solutionwas concentrated, and the aqueous solution of which was adjusted to pH3.3 with citric acidmonohydrate, and then extracted with ethyl acetate(20 mL) twice, and washed with saturated brine, dried over anhydroussodium sulfate, and filtered. The solvent was concentrated under reducedpressure. The resulting residue was subjected to silica gel columnchromatography (ethyl acetate) to afford 1.879 g of the title compound(yield 87%).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 1.50-1.72 (m, 2H), 1.98-2.10 (m,2H), 3.12-3.19 (m, 2H), 4.13-4.20 (m,1H), 4.76 (d, J=11.5 Hz, 1H), 4.70(d, J=11.5 Hz, 1H), 4.85-4.92 (m, 1H), 7.26-7.35 (m, 5H); MS m/z 351[M+H]⁺.

Example 100

Sequential synthesis of(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (IV-a3)

A solution of (2S,5R)-tert-Butyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(66.8 g, 166.0 mmol) described in Example 3 in methylene chloride (135mL) was ice-cooled, and to which was added trifluoroacetic acid (135mL), followed by reacting at the same temperature for 30 min., andfurther at room temperature for 2 h., and then the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate (500 mL), and washed with 25% monosodium citrate (200 mL) andsaturated brine (200 mL), and dried over anhydrous magnesium sulfate,and then solvent was distilled off under reduced pressure. The residuewas dissolved in 1,4-dioxane (133 mL), and to which was added 5M sodiumhydroxide (133 mL) under ice cooling, followed by stirring for 1 h., andthen the mixture was concentrated under reduced pressure. After theaqueous layer was washed with ether (200 mL), pH was adjusted to pH 10by addition of 5M hydrochloric acid (55 mL), and to which were addedpotassium carbonate (23 g) and di-tert-butyl dicarbonate (44 g),followed by stirring overnight. The organic solvent of the mixture wasconcentrated under reduced pressure, and the concentrated mixture waswashed with ether (200 mL). The aqueous layer was adjusted to pH 3.9with citric acid, and extracted with ethyl acetate (500 mL, 250 mL). Theorganic layer was washed with saturated brine (250 mL), and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure to afford 48.02 g of the title compound (yield 83%).Instrumental data were consistent with those of Example 99.

Example 101(2S,5R)-5-((Benzyloxy)amino)-1-(2-trimethylsilylethoxycarbonyl)piperidine-2-carboxylicacid (IV-a4)

To (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylic acid,dihydrochloride (3.23 g, 10 mmol) described in Example 11 were added1,4-dioxane (10 mL), water (15 mL) and 5M sodium hydroxide (6 mL), andstirred under ice cooling. Potassium carbonate (1.38 g),N-(trimethylsilylethyloxycarbonyloxy)succinimide (2.85 g) were addedfurther to the mixture, and the temperature was elevated to roomtemperature, followed by stirring overnight. The mixture was adjusted topH 4 with citric acid monohydrate, and extracted with ethyl acetate (50mL) twice. The organic layer was washed with water and saturated brineand concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography (ethyl acetate/hexane=1:1→1:0) toafford 3.41 g of the title compound (yield 86%).

¹H NMR (400 MHz, CDCl₃) δ 0.01 (s, 9H), 0.97 (t, J=8.3 Hz, 2H),1.59-1.68 (m, 2H), 1.97-2.02 (m, 2H), 3.00-3.25 (m, 2H), 4.08-4.19 (m,3H), 4.65 (d, J=11.3 Hz, 1H), 4.71 (d, J=11.3 Hz, 1H), 4.72-4.89 (m,1H), 7.23-7.32 (m, 5H); MS m/z 395 [M+H]⁺.

Example 102(2S,5R)—N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide(IV-b2-Boc-059)

(2S,5R)-5-(Benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylicacid (0.879 g, 2.54 mmol) described in Example 98 and tert-butyl2-(aminooxy)ethylcarbamate (0.559 g) of Reference Example 9 weredissolved in N,N-dimethylformamide (11 mL), and to which was added1-hydroxybenzotriazole monohydrate (0.489 g), followed by ice-cooling.To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.613 g), and the temperature was elevated to roomtemperature, followed by reacting for 3 h. Water was added to thereacted mixture, and extracted with ethyl acetate. After the organiclayer was washed with 10% citric acid aqueous solution, water, 6.5%sodium bicarbonate aqueous solution and saturated brine sequentially,and then the solvent was distilled off under reduced pressure. Theresulting oil residue was purified by silica gel column chromatography(n-hexane/ethyl acetate=1/2) to afford 1.07 g of the title compound(yield 84%).

¹H NMR (400 MHz, CDCl₃) δ observed as a mixture of 2 rotamers (approx.7:3). 1.26 (m, 0.3H), 1.44 (s, 9H), 1.70 (m, 0.7H), 1.81-2.12 (m, 3H),3.10 (br. d, J=14.4 Hz, 0.3H), 3.30 (m, 3H), 3.54 (br. d, J=12.4 Hz,0.7H), 3.87 (m, 2H), 4.15 (d, J=13.2 Hz, 0.7H), 4.58-4.79 (m, 2.6H),4.90 (m, 0.7H), 4.97 (m, 0.3H), 5.11 (m, 0.7H), 5.33 (m, 1H), 7.26-7.38(m, 5H), 9.75 (br. s, 0.7H), 10.48 (br. s, 0.3H); MS m/z 505 [M+H]⁺.

Example 103(2S,5R)—N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)piperidine-2-carboxamide(IV-c-Boc-059)

(2S,5R)—N-(2-tert-butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide(1.07 g, 2.06 mmol) was dissolved in 1,4-dioxane (4.2 mL), to which wasadded water (1.1 mL), and followed by ice cooling. To this was added 1Msodium hydroxide aqueous solution (6.3 mL), and followed by reaction atthe same temperature for 2.5 h. pH was adjusted to ca. pH 7 by theaddition of acetic acid to the reaction mixture. The organic solvent wasdistilled off under reduced pressure. The resulting aqueous solution wasextracted with ethyl acetate. After the organic layer was washed withsaturated brine, and dehydrated with anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The resulting oilresidue was purified by silica gel column chromatography (ethylacetate/methanol=9/1) to afford 0.80 g of the title compound (yield93%).

¹H NMR (400 MHz, CDCl₃) δ 1.36-1.44 (m, 10H), 1.74 (m, 1H), 1.95 (m,1H), 2.10 (m, 1H), 2.68 (m, 1H), 3.14 (m, 1H), 3.33 (m, 2H), 3.42 (m,1H), 3.50 (m, 1H), 3.88 (m, 2H), 4.66 (s, 2H), 5.49 (br. m, 1H),7.29-7.37 (m, 5H); MS m/z 409 [M+H]⁺.

Example 104 (2S,5R)—N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-[2-(trimethylsilyl)ethyloxycarbonyl]piperidine-2-carboxamide(IV-b4-059)

(2S,5R)-5-(Benzyloxyamino)-14(2-(trimethylsilyl)ethoxy)carbonyl)piperidine-2-carboxylicacid (601 mg, 1.52 mmol) described in Example 101 and tert-butyl2-(aminooxy)ethylcarbamate (303 mg, 1.72 mmol) of Reference Example 9were dissolved in N,N-dimethylformamide (5.8 mL), to which was added1-hydroxybenzotriazole monohydrate (264 mg), followed by ice cooling. Tothis was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimidehydrochloride (330 mg), a temperature was elevated to room temperature,followed by reaction for 5 h. Water was added to the reaction mixtureand extracted with ethyl acetate. After the organic layer was washedwith 10% citric acid aqueous solution, water, 6.5% sodium bicarbonateaqueous solution and saturated brine sequentially, the organic layer wasdehydrated over anhydrous magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. The resulting oil residue waspurified by silica gel column chromatography (n-hexane/ethylacetate=1/2) to afford 450 mg of the title compound (yield 54%).

¹H NMR (400 MHz, CDCl₃) δ 0.01 (s, 9H), 0.98 (m, 2H), 1.42 (s, 9H), 1.58(m, 1H), 1.84-1.96 (m, 3H), 3.04 (m, 1H), 3.18 (br. s, 1H), 3.28 (m,1H), 3.35 (m, 1H), 3.85 (m, 2H), 4.16-4.35 (m, 3H), 4.63-4.75 (m, 3H),5.32-5.70 (br. m, 2H), 4.26-4.33 (m, 5H), 9.44 (br. s, 1H); MS m/z 553[M+H]⁺.

Example 105 Synthesis from tert-Butyl2-((2S,5R)-5-(benzyloxyamino)piperidine-2-carboxamideoxy)ethylcarbamate(IV-c-Boc-059): (IV-b4-Boc-059)

(2S,5R)—N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-[2-(trimethylsilyl)ethyloxycarbonyl]piperidine-2-carboxamide(417 mg, 0.754 mmol) was dissolved in tetrahydrofuran (5.5 mL), to whichwas added 1.0M fluorotetra-n-butylammonium tetrahydrofuran solution (1.9mL), followed by reaction at 50° C. for 24 h. The reaction mixture wasdiluted with ethyl acetate, and washed with 6.5% sodium bicarbonateaqueous solution, water and saturated brine sequentially, after whichtime, the organic layer was dehydrated over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. The resultingoil residue was purified by silica gel column chromatography (ethylacetate ethyl acetate/methanol=9/1) to afford 250 mg of the titlecompound (yield 81%). Instrumental data were consistent with those ofExample 103.

Example 106(2S,5R)—N-(2-Benzyloxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(tert-butoxycarbonyl)piperidine-2-carboxamide(IV-c-Cbz-059)

(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (1.879 g, 5.362 mmol) described in Example 99 or 100, benzyl2-(aminooxy)ethylcarbamate (1.41 g, 6.707 mmol) of Reference Example 11and 1-hydroxybenzotriazole monohydrate (220 mg) were dissolved inmethylene chloride (20 mL), followed by stirring under ice cold. To thiswas added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride(1.29 g), and a temperature was elevated to room temperature, followedby stirring overnight. The mixture was diluted with methylene chloride(20 mL), and washed with water, 10% citric acid aqueous solution,saturated sodium bicarbonate aqueous solution, and saturated brinesequentially, and then dried over magnesium sulfate. The solvent wasconcentrated under reduced pressure to afford 2.91 g of the titlecompound (quantitative).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (s, 9H), 1.50-1.93 (m, 4H), 3.40 (m, 2H),3.89 (m, 2H), 4.15-4.21 (m, 1H), 4.61 (m, 1H), 4.69 (d,J=11.6 Hz,1H),4.76 (d,J=11.6 Hz, 1H),5.11 (s, 2H), 5.86 (s, 1H), 7.27-7.36 (m,5H), 9.28 (s, 1H); MS m/z 543 [M+H]⁺.

Example 107(2S,5R)—N-(2-Benzyloxycarbonylaminoethoxy)-5-(benzyloxyamino)piperidine-2-carboxamide(IV-c-Cbz-059)

(2S,5R)—N-(2-Benzyloxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(tert-butoxycarbonyl)piperidine-2-carboxamide(2.91 g, 5.362 mmol) was dissolved in 1,4-dioxane (5 mL), to which wasadded under ice cooling 4M hydrochloric acid-dioxane solution (10 mL).After stirring for 2 h., the mixture was concentrated under reducedpressure, dissolved in water (30 mL), and washed with ether. The aqueouslayer was ice-cooled, and pH was set to ca. pH 7 with 5M sodiumhydroxide and acetic acid, and then extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate, and then the solvent was concentrated under reducedpressure. The residue was subjected to silica gel column chromatography(chloroform chloroform/methanol=3:1) to afford 2.27 g of the titlecompound (yield 95%).

¹H NMR (400 MHz, CDCl₃) δ 1.22-1.34 (m, 1H), 1.50-1.58 (m, 1H),1.89-1.92 (m, 1H), 1.92-2.06 (m, 1H), 2.43-2.48 (m, 1H), 2.95 (m, 1H),3.23-3.27 (m, 1H), 3.40-3.42 (m, 2H), 3.71-3.73 (m, 2H), 3.89-3.92 (m,2H), 4.66 (s, 2H), 5.11 (s, 2H), 5.91 (s, 1H), 7.26-7.52 (m, 10H); MSm/z 443 [M+H]⁺.

Example 108 Benzyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(IIa-Cbz-059)

A solution of(2S,5R)—N-(2-benzyloxycarbonylaminoethoxy)-5-(benzyloxyamino)piperidine-2-carboxamide(642 mg, 1.451 mmol) in acetonitrile (66 mL) was ice-cooled, and towhich were added triethylamine (709 μL) and chlorotrimethylsilane (203μL), followed by stirring for 1 h. To this reaction solution was addedchloroformate trichloromethyl (105 μL), followed by stirring at the sametemperature for 20 min. To this reaction solution was then4-(dimethylamino)pyridine (18 mg) was added, a temperature was elevatedto room temperature, followed by stirring overnight. The reactionmixture was concentrated under reduced pressure, and the resultingresidue was diluted with ethyl acetate, and then washed with water, 5%citric acid aqueous solution, 6.5% sodium bicarbonate aqueous solutionand saturated brine sequentially. Subsequently, the organic layer wasdehydrated over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (n-hexane/ethyl acetate=1/3) toafford 407 mg of the title compound (yield 60%).

¹H NMR (400 MHz, CDCl₃) δ 1.59-1.65 (m, 1H), 1.91-2.02 (m, 2H),2.26-2.31 (m, 1H), 2.71-2.74 (d, J=11.6 Hz, 1H), 2.99-3.02 (br d, J=11.2Hz, 1H), 3.28 (s, 1H), 3.31-3.39 (m, 1H), 3.46-3.49 (m, 1H), 3.88-3.97(m, 3H), 4.88-4.91 (d, J=11.6 Hz, 1H), 5.03-5.06 (d, J=11.6 Hz, 1H),5.11 (s, 2H), 5.83 (br s, 1H), 7.27-7.43 (m, 10H), 9.36 (br s, 1H); MSm/z 469 [M+H]⁺.

Example 109(2S,5R)—N-(2-tert-Butoxycarbonylaminoethoxy)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(IIa-Boc-059)

A solution of(2S,5R)—N-(2-tert-butoxycarbonylaminoethoxy)-5-(benzyloxyamino)piperidine-2-carboxamide(368 mg, 0.901 mmol) described in Example 103 or 105 in acetonitrile(40.9 mL) was ice-cooled, and to which were added triethylamine (440 μL)and chlorotrimethylsilane (126 μL), followed by stirring for 1 h. Tothis reaction solution was added trichloromethyl chloroformate (66.0 μL)was added, followed by stirring at the same temperature for 30 min. Thento this reaction solution was added 4-(dimethylamino)pyridine (10.2 mg),and a temperature was elevated to room temperature, followed by reactionfor 4 hr. The reaction mixture was concentrated under reduced pressure,and the resulting residue was diluted with ethyl acetate, and thenwashed with water, 5% citric acid aqueous solution, 6.5% sodiumbicarbonate aqueous solution and saturated brine sequentially. Then, theorganic layer was dehydrated over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The resulting oilresidue was purified by silica gel column chromatography (n-hexane/ethylacetate=2/3) to afford 202 mg of the title compound as a colorless solid(yield 52%). Instrumental data were consistent with those of Example 59.

Example 110 tert-Butyl{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(IIb-Boc-059)

tert-Butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(43.4 g, 100 mmol) was dissolved in tetrahydrofuran (475 mL). After thedissolution was confirmed, water (25 mL) was added, and set under anargon atmosphere. 10% Pd/C (8.68 g, 50% wet) was added, and stirredvigorously under hydrogen atmosphere for 3 h. The end point wasconfirmed by TLC, and then catalyst was filtered through Celite. Thesolvent of filtrate was concentrated under reduced pressure. Theconcentrated residue was subjected to workup of substitution andconcentration with ethyl acetate (100 mL) twice, and with methylenechloride (100 mL) once to afford 34.5 g of the title compound(quantitative). Instrumental data were consistent with those of Example59.

Example 111 tert-Butyl{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(IIb-Boc-059): Synthesis from (IIa-Cbz-059)

Benzyl{12-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(468 mg, 1.00 mmol) described in Example 108 anddi-tert-butoxycarbonyldicarbonate (240 mg) were dissolved intetrahydrofuran (6.6 mL), and to which was added 10% Pd/C (93 mg, 50%wet), followed by stirring vigorously under an hydrogen atmosphere for 3h. The end point was confirmed by TLC, and then catalyst was filteredthrough Celite. The solvent of filtrate was concentrated under reducedpressure to afford 403.7 mg of the title compound (quantitative).Instrumental data were consistent with those of Example 59.

Example 112 Tetrabutylammonium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(III-Boc-059)

To a solution of tert-butyl{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(34.5 g, 100 mmol) in methylene chloride (500 mL) were added2,6-lutidine (32.8 g) and sulfur trioxide-pyridine complex (51.9 g)sequentially, and stirred for 24 hours. Completion of reaction wasconfirmed by HPLC, the reaction solution was filtered, and filtrate wasadded into 8% sodium bicarbonate aqueous solution (1 L), and washed withmethylene chloride (500 mL). To the aqueous layer was added ethylacetate (1 L), followed by addition of tetrabutylammonium hydrogensulfate (37.34 g) while paying attention to effervescence, and stirredfor 30 min. Following liquid separation of the mixture, the aqueouslayer was extracted with ethyl acetate (500 ml) twice. The combinedorganic layers were dried over magnesium sulfate, and the solvent wasconcentrated under reduced pressure to afford 53.9 g of the titlecompound (yield 81.1%). Instrumental data were consistent with those ofExample 59.

Example 113(2S,5R)—N-(2-Aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

A solution of tetrabutylammonium tert-butyl{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate(68.9 g, 104 mmol) in methylene chloride (170 mL) solution was cooled to−20° C., and trifluoroacetic acid (170 mL) was added at −15° C. or lessover 20 min., followed by stirring at 0° C. for 35 min. To the reactionsolution was added diethyl ether (510 mL), and followed by stirring at0° C. for 40 min. The precipitated solid was filtered through Kiriyamafunnel, and washed with diethyl ether (450 mL), subsequently dried undervacuo to afford a crude product (39.5 g). This was added to 0.5M sodiumacetate/acetic acid buffer (400 mL, pH 5.6), and further pH was adjustedto pH 5.6 with 5M sodium hydroxide aqueous solution, and then waspurified by octadecyl silica gel column chromatography (water) to afford24.8 g of the title compound (yield 74%). Instrumental data wereconsistent with those of Example 59.

Example 114 Dihydrochloride of (2S,5R)-methyl5-(benzyloxyamino)piperidine-2-carboxylate (4b); Synthesis from thecompound (2) through hydrochloride of(2S,5S)-5-hydroxypiperidine-2-carboxylic acid (7) Step 1 Hydrochlorideof (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (7)

(2S,5S)-tert-Butyl S-hydroxypiperidine-2-carboxylate (126.22g, 0.63 mol)described in Example 1 was gradually added into 5M hydrochloric acid(630 mL) at room temperature, followed by heating to 65° C. and stirringfor 2 hours. Subsequently, the reaction solution was cooled to roomtemperature and the reaction solvent was concentrated under reducedpressure. The residue was dissolved in water (500 mL), and activatedcarbon (6.5 g) was added, followed by stirring at room temperature for30 minutes. The activated carbon was filtered through Celite. Celite waswashed twice with water (100 mL) and the filtrate was combined, followedby concentrating under reduced pressure. The residue (150 g) wasice-cooled, followed by inoculation and stirring. To the mixture wasadded dropwise acetone (650 mL) over 30 minutes, followed by stirringfor 30 minutes. The deposited crystals were filtered off under an argonstream, followed by washing with acetone. After deliquoring and dryingunder vacuum overnight, 108.79 g of the title compound was afforded as acolorless powder crystal (yield 96%).

¹H NMR (400 MHz, D₂O) 5 1.66-2.23 (m, 4H), 3.25 (d, J=3.4 Hz, 1H), 3.38(d, J=3.4 Hz, 1H), 4.00 (dd, J=11.7, 3.7 Hz, 1H), 4.22 (brs, 1H); MSm/z: 146 (M−HCl+H)⁺.

Step 2 Hydrochloride salt of (2S,5S)-methyl5-hydroxypiperidine-2-carboxylate (8)

To (2S,5S)-5-hydroxypiperidine-2-carboxylic acid hydrochloride salt(26.46 g, 0.146 mol) was added 2M hydrogen chloride-methanol (230 mL),followed by heating at reflux. After 1.5 hours, the reaction solutionwas concentrated, followed by substituting and concentrating withmethanol (200 mL) three times. The residue was dried under vacuum toafford 28.55 g of the title compound as a colorless crystalline powder(quantitative yield).

¹H NMR (400 MHz, D₂O) 5 1.74-2.06 (m, 4H), 3.12 (dd, J=2.0, 13.2 Hz,1H), 3.25-3.29 (m, 1H), 3.72 (s, 3H), 3.98 (dd, J=3.8, 12.2 Hz, 1H),4.09 (brs, 1H); MS m/z: 160 (M−HCl+H)⁺.

Step 3 (2S,5S)-Methyl 5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (9)

To a suspension of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylatehydrochloride (26.80 g, 0.137 mol) in dehydrated tetrahydrofuran (440mL) was added triethylamine (91.0 mL) under ice cooling, followed byadding dropwise trifluoroacetic anhydride (39.5 mL) at 10° C. or lessover 1 hour. The reaction suspension was stirred for 70 minutes whilethe temperature was gradually elevated to room temperature. To thereaction solution was added water (80 mL), followed by stirring at roomtemperature for 30 minutes. Subsequently, it was added to water (1000mL) and extracted with ethyl acetate three times (500 mL+2×250 mL). Theorganic layer was washed with 1M hydrochloric acid (300 mL), a saturatedsodium bicarbonate aqueous solution (200 mL) and saturated brine (2×150mL), dried over anhydrous sodium sulfate, filtered, and thenconcentrated under reduced pressure to afford 34.65 g of the titlecompound as an oil (yield 99%).

¹H NMR (400 MHz, CDCl₃) δ observed as a mixture of 2 rotamers (7:3).1.34-1.44 (m, 1H), 1.73-1.83 (m, 1H), 2.00-2.10 (m, 2H), 2.39-2.45 (m,1H), 2.75 (t, J=11.5 Hz, 0.3H), 3.11 (dd, J=5.7, 13.4 Hz, 0.7H), 3.79(s, 2.1H), 3.81 (s, 0.9H), 4.00-4.06 (m, 0.7H), 4.58-4.67 (m, 0.3H),4.62 (m, 0.3H), 5.20 (d, J=5.9 Hz, 0.7H); MS m/z: 256 (M+H)⁺.

Step 4 Hydrochloride of (2S,5R)-methyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(10)

A solution of (2S,5S)-methyl5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (32.71g,0.128 mol) in dehydrated acetonitrile (250 mL) was cooled to −30° C.,followed by adding 2,6-lutidine (16.9 mL) and adding dropwisetrifluoromethanesulfonic anhydride (22.5 mL) at −36 to −30° C. over 15minutes. After stirring at −32° C. for 25 minutes, benzyloxyamine (32.25g) was added dropwise at −32° C. or less, followed by washing withacetonitrile (10 mL). After the reaction solution was gradually warmedto 0° C., 2,6-lutidine (16.9 mL) was added and stirred at 4° C. for 2days. The reaction solution was concentrated to 150 mL, followed bydiluting with ethyl acetate (750 mL) and washing with water (750 mL),10% citric acid aqueous solution (3×750 mL), a saturated sodiumbicarbonate aqueous solution (375 mL), and saturated brine (400 mL).Each aqueous layer was reextracted with ethyl acetate (400 mL) and thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure to afford 46.93 gof the residue. 38.24 g of the resulting residue was taken out anddiluted with ethyl acetate (120 mL). At room temperature, 1M hydrogenchloride-ethyl acetate 160 mL (0.160 mol) was added for crystallization,and hexane (560 mL) was added. After stirring at 0° C. for 3 hours, thecrystals were filtered, washed with hexane (400 mL), and then driedunder vacuum to afford 30.36 g of the title compound as a crystallinepowder (yield 73%).

¹H NMR (400 MHz, CD₃OD) δ observed as a mixture of 2 rotamers. 2.00-2.09(m, 3H), 2.23-2.24 (m, 1H), 3.33-3.42 (m, 0.5H), 3.74 (dd, J=3.2, 15.6Hz, 0.5H), 3.79 (s, 2H), 3.81 (s, 1H), 3.89 (brs, 1H), 4.29 (d, J=15.9Hz, 0.5H), 4.81 (d, J=14.4Hz, 0.5H), 5.08-5.16 (m, 2.5H) ; MS m/z: 361(M−HCl+H)⁺.

Step 5 Dihydrochloride of (2S,5R)-methyl5-(benzyloxyamino)piperidine-2-carboxylate (4b)

To (2S,5R)-methyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylatehydrochloride salt (1.951g, 4.92 mmol) was added 2M hydrogenchloride-methanol (40 mL), followed by refluxing for 3 days.Subsequently, the reaction solution was concentrated to 14 mL, and ethylacetate (40 mL) was added to deposit a crystal. The suspension wasstirred at room temperature for 1.5 hours, then filtered throughKiriyama funnel, washed with ethyl acetate (80 mL), and dried undervacuum to afford 1.439 g of the title compound as a crystalline powder(yield 87%). The instrumental data were consistent with those of Example12.

Example 115 Dihydrochloride of(2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate (4b); Synthesis fromcommercially available (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (7)Step 1 Hydrochloride of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate(8)

To 2M hydrogen chloride-methanol (12.8 L) was added commerciallyavailable (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (content 84%,net 912.22 g, washed with 2M hydrogen chloride-methanol 3.1 L), followedby refluxing for 3 hours (internal temperature 63-67° C.). After thereaction solution was cooled, 1,4-dioxane (12.8 L) was added and thesolvent was distilled off under reduced pressure. To the residue (4.1kg) were added ethyl acetate (18.3 L) and ice-cooled 44% potassiumcarbonate aqueous solution (23.7 L), followed by layer separation of theorganic layer. The aqueous layer was further extracted with ethylacetate (3×18.3 L). A 50% potassium carbonate aqueous solution (7.3 L)was separated at each organic layer, the organic layers were combined,dried over anhydrous potassium carbonate (2.37 kg) and filtered, and thesolvent was distilled off under reduced pressure. The residue wasdissolved in toluene (9.1 L), and activated carbon (9.2 g) was added,followed by stirring for 30 minutes and filtering, and the solvent wasdistilled off under reduced pressure. The residue was substituted withethyl acetate (9.1 L) and concentrated to afford 1130 g of the titlecompound as a pale yellow oil (content 78.9%, net 891.57 g, yield 89%).

Step 2 (2S,5S)-Methyl5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (9)

A solution of (2S,5S)-methyl 5-hydroxypiperidine-2-carboxylate (content78.8%, net 459.48 g) in dehydrated ethyl acetate (7.4 L) was cooled to−40° C. and triethylamine (1300 g) and then trifluoroacetic anhydride(1349 g), washed with dehydrated ethyl acetate (100 mL) were addeddropwise at −40 to −12° C. for 30 minutes. The temperature was elevatedto −2° C. within 15 minutes after completion of the dropwise addition,followed by stirring for 75 minutes. Further, to the mixture was addedwater (1277 mL), followed by stirring at 25° C. for 1 hour. The mixturewas added to water (8.4 L) (washed with ethyl acetate (4.5 L), followedby further extracting with ethyl acetate (2×9.8 L). The combined organiclayers were sequentially washed with 1M hydrochloric acid (8.5 L),saturated sodium bicarbonate aqueous solution (8.5 L) and saturatedbrine (8.5 L), followed by drying over anhydrous sodium sulfate (1.8 kg)and filtering. After the solvent of the organic layer was distilled offunder reduced pressure, to the residue was added ethyl acetate (3.6 L),followed by substitution and concentration. The residue was dried undervacuum to afford 793.4 g of the title compound (content 81.5%, net648.66 g, yield 88%).

Step 3 (2S,5R)-Methyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(10)

A solution of (2S,5S)-methyl5-hydroxy-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate (content81.5%, net 556.23 g) in dehydrated acetonitrile (4.0 L) was cooled to−40° C., 2,6-lutidine (259.24 g) was added (washed with acetonitrile(100 ml), and trifluoromethane sulfonic acid anhydride (645.72 g) wasadded dropwise at −43 to −37° C. over 1 hour and 10 minutes (washed withacetonitrile 100 ml). After the reaction solution was stirred at −35° C.for 50 minutes, benzyloxyamine (550.27 g) was added dropwise at −35° C.or less, followed by washing with acetonitrile (500 mL). After thereaction solution was gradually warmed to −5° C., 2,6-lutidine (259.24g) was added, followed by stirring at 5° C. for 40 hours. The mixturewas concentrated to 1.8 L, followed by diluting with ethyl acetate (12.4L) and washing with water (12.4 L), a 10% citric acid aqueous solution(4×8 L+4.7 L), saturated sodium bicarbonate aqueous solution (6.3 L) andsaturated brine (7.2 L). The organic layer was dried over anhydroussodium sulfate, followed by filtering and then concentrating underreduced pressure. The residue was dried under vacuum to afford 867.73 gof the title compound (content 71.56%, yield 79%).

Step 4 Hydrochloride of (2S,5R)-methyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(10)

(2S,5R)-Methyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(content 70.13%, net 673.20 g) was diluted with ethyl acetate (4.8 L)and activated carbon (48 g) was added, followed by stirring for 1 hour.The mixture was filtered, followed by washing with ethyl acetate (2 L).The filtrate was diluted with ethyl acetate (4.7 L), and 1M hydrogenchloride-ethyl acetate solution (2.7 L) at room temperature was added,followed by stirring for 15 minutes. Then, hexane 28.6 L was added,followed by cooling to 0° C. After stirring and aging for 3 hours, thecrystals were filtered, washed with hexane/ethyl acetate=4/1 (3 L), andthen dried under vacuum to afford 724.0 g of the title compound (content91.72%, yield 90%).

Step 5 Dihydrochloride of (2S,5R)-methyl5-(benzyloxyamino)piperidine-2-carboxylate (4b)

(2S,5R)-Methyl5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate(content 92.01%, net 732.25 g) was dissolved in a 2M hydrogenchloride-methanol solution (15 L), followed by heating at reflux for 27hours. The mixture was cooled to room temperature and concentrated to 3L under reduced pressure. To the mixture was added methanol (2.7 L),then ethyl acetate (16.3 L) was added, followed by stirring for 1 hour.The deposited crystals were filtered, washed with ethyl acetate (3×1.1L), and dried under vacuum to afford 572.0 g of the title compound(content 98.06%, yield 92%). The instrumental data were consistent withthose of Example 12.

Example 116(2S,5R)-5-((Benzyloxy)amino)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (IV-a3)

Dihydrochloride of (2S,5R)-methyl5-(benzyloxyamino)piperidine-2-carboxylate (4b) described in Example 12(6.64 g, 20 mmol) was dissolved in water (40 mL) and 1,4-dioxane (27mL), followed by ice cooling. A 5M aqueous sodium hydroxide (13.2 mL)solution was added, followed by stirring for 1 hour. To the reactionsolution were added 5M hydrochloric acid (1.2 mL), potassium carbonate(2.76 g), di-tert-butoxycarbonyl dicarbonate (4.8 g), followed byraising the temperature to room temperature and stirring overnight. Theaqueous solution resulting from concentration of the reaction solutionwas washed with ether, followed by adjusting to pH 3.3 with citric acidmonohydrate, extracting with ethyl acetate (50 mL) twice, washing withsaturated brine, drying over anhydrous sodium sulfate, filtering, andconcentrating the solvent under reduced pressure. Thereby, 6.87 g of thetitle compound was affored (quantitative yield). The instrumental datawere consistent with those of Example 99.

Example 117 Preparation of β-Lactamase Enzyme

Using Pseudomonas aeruginosa ATCCBAA-47 genome, plasmid pBR322,Klebsiella pneumoniae ATCCBAA-1705, and P. aeruginosa MSC17696 as atemplate, each DNA for encoding β-lactamase, AmpC, TEM-1, KPC-2 or OXA-2domain excluding signal peptide was amplified with PCR. Each of the PCRproduct was incorporated into pET-28b(+)vector (Merck), introduced intoEscherichia coli BL21 (DE3) (Merck), and, under induction of 1 mMisopropyl-(3-D-(−)-thiogalactopyranoside (Nacalai Tesque), culturedovernight at 20° C. to express AmpC, TEM-1, KPC-2, and OXA-2. After thebacterial cell was collected, AmpC was purified from the cell extractobtained by ultrasonic treatment, using CM Sepharose Fast Flow (GEHealthcare) and HiTrap Heparin HP (GE Healthcare) at 4° C. TEM-1 waspurified with HiTrap SPHP (GE Healthcare), HiTrap Q (GE Healthcare) andMono Q (GE Healthcare), and KPC-2 was purified with HiTrap SPHP. OXA-2was purified with HiTrap SPHP and HiTrap Heparin HP.

Example 118 β-Lactamase Inhibitory Activity

For the measurement of β-lactamase inhibitory activity, 100 μM (finalconcentration) nitrocefin (Oxoid) was used as a substrate, and 2.5%DMSO, 10 μg/mL bovine serum derived albumin (Sigma-Aldrich) and 50 mMphosphate buffer at pH 7.0 were used as a reaction solution. To eachwell of a 96-well plate were added test compounds, tazobactam (TAZ, LKTLaboratories), NXL104 (prepared by reference to Patent document 1,purity 99.5%, Meiji Seika Pharma Co., Ltd.) or MK-7655 (prepared byreference to Patent document 3, purity 99.4%, Meiji Seika Pharma Co.,Ltd.) and AmpC, TEM-1, KPC-2 or OXA-2 (final concentrations are 0.5 nM,0.1 nM, 0.5 nM, or 2 nM, respectively), followed by pre-incubation at30° C. for 10 minutes. Nitrocefin was added to each well to be mixedtherein, followed by incubation at 30° C. for 20 minutes, and MultiscanAscent (Thermo Fisher Scientific) was used to measure 492 nm wavelength,thereby measuring nitrocefin hydrolytic activity of β-Lactamase, todetermine enzyme inhibitory activity. As a control, a reaction solutionexcluding β-lactamase was prepared, and the concentration of a testcompound exhibiting 50% inhibition was determined to be IC50 value. Asthe inhibitory activity strength, less than 0.1 μM, less than 1 μM, lessthan 3 μM, less than 10 μM, and 10 μM or more were shown with A, B, C,D, and E respectively. The results are as shown in Table 5.

Class A β-Lactamase: KPC-2, TEM-1

Class C β-Lactamase: AmpC

Class D β-Lactamase: OXA-2 (ESBL)

TABLE 5 β-Lactamase inhibitory activity Compound AmpC TEM-1 KPC-2 OXA-2TAZ B A B A NXL104 B A B B MK-7655 B A B B Example 17 B A B D Example 18B A B C Example 19 B A B NT Example 20 B B C D Example 21 B A B CExample 22 B A B D Example 23 B A B D Example 24 B B B NT Example 25 B AA E Example 26 C B C NT Example 27 B A C C Example 28 A A B D Example 29B A B D Example 30 B A B NT Example 31 B A B D Example 32 A A B DExample 33 B A B D Example 34 A A B D Example 35 B A D C Example 36 B AC D Example 37 C A C C Example 38 B A B C Example 39 A A C C Example 40B A D C Example 41 B B C D Example 42 B B B C Example 43 B A B C Example44 A A A C Example 45 A A B C Example 46 A A B C Example 47 B A B DExample 48 A B B D Example 49 B A B D Example 50 A B B D Example 51 B AB C Example 52 B A B C Example 53 B A B NT Example 54 A A B B Example 55B B C D Example 56 B A B C Example 57 B A C NT Example 58 A A A BExample 59 B A B C Example 60 B A B B Example 61 B A C C Example 62 B AB C Example 63 B A B C Example 64 B A B C Example 65 B B C C Example 66B A C C Example 67 B A C C Example 68 A A B C Example 69 B A C B Example70 B A B B Example 71 B A B NT Example 72 A A B B Example 73 A A B NTExample 74 A A B B Example 75 B A B C Example 76 B A B B Example 77 B AB B Example 78 B A C C Example 79 B A C C Example 80 B A C B Example 81A A B C Example 82 A A B B Example 83 A A B B Example 84 A A C B Example85 A A B B Example 86 A A B NT Example 87 A A A B Example 88 B A B BExample 89 A A A B Example 90 A A B B Example 91 A A A B Example 92 A AB B Example 93 A A B B Example 94 A A B B Example 95 A A A C Example 96A A B C Example 97 A A A B NT: Not tested; A: <0.1 μM, B: <1 μM, C: <3μM, D: <10 μM, E: ≥10 μM

Example 119 Synergetic Effect

The synergetic effect of the test compound with a β-lactam agent againstbacteria was evaluated using AmpC constitutively-expressing strain, P.aeruginosa ATCCBAA-47CR selected from ATCCBAA-47 through agent exposure,KPC-2 producing strain, K. pneumoniae ATCCBAA-1705, and CTX-M-15 (ESBL)and OXA-1 producing strain, E. coli MSC19503. Using piperacillin (PIPC,Sigma-Aldrich) as a β-lactam agent, minimal inhibitory concentration(MIC) of PIPC was measured by agar plate dilution process based onClinical and Laboratory Standards Institute (CLSI process). That is, anagar plate containing PIPC at each concentration adjusted in commonratio 2 of dilution series in Mueller-Hinton agar (MHA, Becton,Dickinson and Company) and the test compound having 1/4 or 1/8 ofrespective PIPC concentration was made, and bacteria cultured overnightin cation-adjusted Muller-Hinton broth (CAMHB, Becton, Dickinson andCompany) were adjusted in the same medium so as to have 10⁴ CFU/spot andinoculated on a plate containing an agent. This plate containing anagent was cultured overnight at 35° C., and the minimum agentconcentration in which no growth of bacteria was observed was determinedto be MIC. The antibacterial activities of PIPC alone to AmpCconstitutively-expressing, P. aeruginosa, KPC-2 producing K. pneumoniae,and CTX-M-15 (ESBL) and OXA-1 producing E. coli were shown by 64μg/mL, >128 μg/mL, >128 μg/mL respectively, and those in whichantibacterial activities of PIPC were recovered by less than 1/16, lessthan 1/4, and less than 1/1, and were not recovered, by the synergeticeffect of the test compounds were shown with A, B, C, and Drespectively. The results are as shown in Table 6.

Class A β-Lactamase: KPC-2, CTX-M-15 (ESBL)

Class C β-Lactamase AmpC

Classe D β-Lactamase: OXA-1

TABLE 6 Organism P. aeruginosa K. pneumoniae E. coli Bacterial strainATCCBAA- ATCCBAA- 47CR 1705 MSC19503 Producing enzyme Compound/CTX-M-15, PIPC AmpC(++) KPC-2 OXA-1 Compound ratio Enhancing activityTAZ 1/8 D D B NXL104 1/8 B B A Example 17 1/8 B B A Example 18 1/4 D C BExample 19 1/4 C B A Example 20 1/4 C B A Example 21 1/8 C A A Example22 1/8 C A A Example 23 1/8 C B A Example 24 1/8 C C B Example 25 1/4 CB A Example 26 NT NT NT NT Example 27 1/8 C A A Example 28 1/8 C A AExample 29 1/8 C B A Example 30 1/4 D C B Example 31 1/8 C B A Example32 1/4 C B A Example 33 NT NT NT NT Example 34 1/8 C B A Example 35 1/8B A A Example 36 1/8 C A A Example 37 1/8 C B A Example 38 1/8 C A AExample 39 1/8 C B A Example 40 1/8 C B A Example 41 1/8 C A A Example42 1/8 C B A Example 43 1/8 C B A Example 44 1/8 C B B Example 45 1/8 CB A Example 46 1/8 C B A Example 47 1/8 C B B Example 48 1/8 C C BExample 49 1/4 D B A Example 50 1/8 C B A Example 51 1/8 C B A Example52 1/8 C B A Example 53 1/4 C C B Example 54 1/8 C B A Example 55 NT NTNT NT Example 56 1/8 C B A Example 57 1/4 C B A Example 58 1/8 C C AExample 59 1/8 B B A Example 60 1/8 D C B Example 61 1/8 B A A Example62 1/8 C B A Example 63 1/8 C B A Example 64 1/8 C A A Example 65 1/8 CA A Example 66 1/8 B B A Example 67 1/8 B A A Example 68 1/8 B B BExample 69 1/8 B B A Example 70 1/8 C B A Example 71 1/8 D C B Example72 1/8 C B A Example 73 1/8 C B A Example 74 1/8 C B A Example 75 1/8 BA A Example 76 1/8 C A A Example 77 1/8 B A A Example 78 1/8 C A AExample 79 1/8 B B A Example 80 1/8 C B A Example 81 1/8 B B B Example82 1/8 B B A Example 83 1/8 C B A Example 84 1/8 B B A Example 85 1/8 BB A Example 86 1/8 C B A Example 87 1/8 C B A Example 88 1/8 D B AExample 89 1/8 C B A Example 90 1/8 C B A Example 91 1/8 C B A Example92 1/8 B B A Example 93 1/8 C B A Example 94 1/8 D C A Example 95 1/8 CB A Example 96 1/8 C B A Example 97 1/8 C B A NT: Not tested; A: < 1/16,B: <¼, C: <1, D: ≥1

Example 120

The synergistic effect of the test compounds synthesized in Examples 59,61 and 69 with a β-lactam agent against bacteria was evaluated usingKPC-2 producing strain, K. pneumoniae ATCCBAA-1705, CTX-M-15 (ESBL) andOXA-1 producing strain, E. coli MSC19503, and AmpCconstitutively-expressing strain, P. aeruginosa ATCCBAA-47CR. Usingampicillin (ABPC, Sigma-Aldrich), amoxicillin (AMPC, Sigma-Aldrich),piperacillin (PIPC), ceftazidime (CAZ, Sigma-Aldrich), cefepime (CFPM,United States Pharmacopeial Convention), cefotaxime (CTX,Sigma-Aldrich), ceftriaxone (CTRX, Sigma-Aldrich), imipenem (IPM, UnitedStates Pharmacopeial Convention), biapenem (BIPM, Meiji Seika PharmaCo., Ltd.), meropenem (MEPM, United States Pharmacopeial Convention),doripenem (DRPM, Sequoia Research Products), cefminox (CMNX, Meiji SeikaPharma), flomoxef (FMOX, SHIONOGI & CO., Ltd.), aztreonam (AZT, UnitedStates Pharmacopeial Convention) as a β-lactam agent, MIC of eachβ-lactam agent was measured by broth microdilution method based on CLSIprocess. That is, a liquid medium containing 4 μg/mL (finalconcentration) of test compound, TAZ, NXL104, or MK-7655, and β-lactamagent and test compound at each concentration adjusted in common ratio 2of dilution series in CAMHB was made, and bacteria cultured overnight inCAMHB were adjusted in the same medium so as to have 10⁵ CFU/mL andinoculated on a liquid medium containing an agent. This liquid mediumcontaining an agent was cultured overnight at 35° C., and the minimumagent concentration in which no growth of bacteria was observed wasdetermined to be MIC. The results are as shown in Tables 7 to 9.

TABLE 7 Synergetic MIC (μg/mL) Organism, bacterial strain (ProducingExample Example Example enzyme) Antibiotic alone 59 61 69 TAZ NXL104MK-7655 P. ABPC >64 64 >64 >64 >64 >64 >64 aeruginosa AMPC >64 64 6464 >64 >64 64 PAO1CR PIPC >64 4 4 4 >64 8 8 (AmpC) CAZ 64 2 2 2 32 2 2CFPM 16 2 2 2 16 2 2 CTX >64 16 16 16 >64 64 16 CTRX >64 16 16 8 >64 3216 IPM 1 0.25 0.5 0.5 1 0.25 0.25 BIPM 0.5 0.25 0.25 0.25 0.5 0.25 0.25MEPM 1 0.5 0.5 1 1 0.5 0.5 DRPM 1 0.25 0.5 0.5 1 0.25 0.25CMNX >64 >64 >64 >64 >64 >64 >64 FMOX >64 >64 >64 >64 >64 >64 >64 AZT 324 4 8 32 8 4

TABLE 8 Synergetic MIC(μg/mL) Organism, bacterial strain (ProducingExample Example Example enzyme) Antibiotic alone 59 61 69 TAZ NXL104MK-7655 K. ABPC >64 ≤0.031 ≤0.031 ≤0.031 >64 16 64 pneumoniae AMPC >64≤0.031 ≤0.031 ≤0.031 >64 32 >64 MSC19408 PIPC >64 ≤0.031 ≤0.031≤0.031 >64 8 32 (KPC-2) CAZ >64 ≤0.031 ≤0.031 ≤0.031 >64 0.5 2 CFPM >64≤0.031 ≤0.031 ≤0.031 >64 ≤0.031 0.25 CTX >64 ≤0.031 ≤0.031 ≤0.031 >640.063 0.5 CTRX >64 ≤0.031 ≤0.031 ≤0.031 >64 0.063 0.5 IPM 8 ≤0.031≤0.031 ≤0.031 4 0.125 0.063 BIPM 16 ≤0.031 ≤0.031 ≤0.031 8 0.125 0.063MEPM 16 ≤0.031 ≤0.031 ≤0.031 4 ≤0.031 ≤0.031 DRPM 8 ≤0.031 ≤0.031 ≤0.0314 ≤0.031 ≤0.031 CMNX 16 ≤0.031 ≤0.031 ≤0.031 16 0.25 2 FMOX >64 ≤0.031≤0.031 ≤0.031 32 0.063 0.5 AZT >64 ≤0.031 ≤0.031 ≤0.031 >64 0.063 0.5

TABLE 9 Synergetic MIC (μg/mL) Organism, bacterial strain (ProducingExample Example Example enzyme) Antibiotic alone 59 61 69 TAZ NXL104MK-7655 E. coli ABPC >64 ≤0.031 ≤0.031 ≤0.031 >64 4 >64 MSC19503AMPC >64 ≤0.031 ≤0.031 ≤0.031 >64 4 >64 (CTX-M- PIPC >64 ≤0.031 ≤0.031≤0.031 >64 4 >64 15, OXA-1) CAZ >64 ≤0.031 ≤0.031 ≤0.031 0.5 0.25 1CFPM >64 ≤0.031 ≤0.031 ≤0.031 0.25 ≤0.031 0.125 CTX >64 ≤0.031 ≤0.031≤0.031 0.25 ≤0.031 1 CTRX >64 ≤0.031 ≤0.031 ≤0.031 0.25 ≤0.031 1 IPM0.25 ≤0.031 ≤0.031 ≤0.031 0.125 0.25 0.25 BIPM 0.25 ≤0.031 ≤0.031 ≤0.0310.125 0.25 0.25 MEPM ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031DRPM ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 ≤0.031 CMNX 1 ≤0.031≤0.031 ≤0.031 1 0.125 0.5 FMOX 0.25 ≤0.031 ≤0.031 ≤0.031 0.25 ≤0.0310.125 AZT >64 ≤0.031 ≤0.031 ≤0.031 0.25 0.063 0.5

Example 121

The synergetic effect of the test compounds synthesized in Examples 59,61, and 69 with a β-lactam agent against bacteria was evaluated using 5strains from each of KPC-2 or 3 producing strain, K. pneumoniae, AmpCconstitutively-expressing strain, P. aeruginosa, AmpCconstitutively-expressing strain, Enterobacteriaceae, IMP typemetallo-β-lactamase producing strain, Enterobacteriaceae, CTX-M-15(ESBL) producing strain, E. coli. Using PIPC as a β-lactam agent, MIC ofthe β-lactam agent was measured by agar plate dilution process based onCLSI process. That is, an agar plate containing 4 μg/mL (finalconcentration) of test compound, TAZ, NXL104 or MK-7655 and β-lactamagent and test compound at each concentration adjusted in common ratio 2of dilution series in MHA was made, and bacteria cultured overnight inCAMHB were adjusted in the same medium so as to have 10⁴ CFU/spot andinoculated on a plate containing an agent. This plate containing anagent was cultured overnight at 35° C., and the minimum agentconcentration in which no growth of bacteria was observed was determinedto be MIC. The results are as shown in Tables 1 to 5.

Example 122 Anti-Tubercle bacillus Activity Measurement

The combinatorial effect of the compound of Example 59 with a β-lactamagent against tubercle bacillus was evaluated using clinical isolates ofmulti-drug resistant tuberculosis (MDR-TB), extensively drug-resistanttuberculosis (XDR-TB), and sensitive tuberculosis (H37Rv). Usingmeropenem (MEPM), biapenem (BIPM), tebipenem (TBPM, Meiji Seika Pharma),ampicillin (ABPC), amoxicillin (AMPC) as a β-lactam agent, MIC of eachβ-lactam agent was measured by a liquid medium dilution method based ona process of BrothMIC MTB-I (Kyokuto Pharmaceutical Industrial Co.,Ltd.) process. That is, a liquid medium containing 4 μg/mL (finalconcentration) of the compound of Example 59 and β-lactam agent at eachconcentration adjusted in common ratio 2 of dilution series in aMiddlebrook 7H9 liquid medium (Becton, Dickinson and Company) containing5% Bovine serum albumin, 2% Dextrose, 0.005% Bovine liver catalase, and0.05% Tween-80 was made, and bacterial suspension adjusted toOD₆₆₀=0.16-0.2 was inoculated by 200-fold dilution. This was culturedfor 7 days at 37° C. under humidified condition, and the minimum agentconcentration in which no growth of bacteria was observed was determinedto be MIC.

As a result, the antibacterial activities (μg/mL) of β-lactam agentalone to MDR-TB, XDR-TB, and H37Rv were shown by 16, 4, and 1 for MEPM,16, 2, and 1 for BIPM, 4, 1, and 0.5 for TBPM, 128, 32, and 16 for ABPC,and 128, 64, and 16 for AMPC, and the antibacterial activities incombinatorial use with the compound of Example 59 were shown by 8, 1,and 0.5 for MEPM, 4, 1, and 1 for BIPM, 2, 0.5, and 0.25 for TBPM, 32,16, and 2 for ABPC, and 64, 16, and 2 for AMPC.

1. A process for preparing a diazabicyclooctane compound represented bythe following formula (I):

wherein A represents RcO—; B represents NH or NC₁₋₆ alkyl; C representsa benzyl group; Rc represents a C₁₋₆ alkyl group; A is substituted withone substituent Fn1, wherein Fn1 represents an azetidine group, theprocess comprising: (a) silylating a compound represented by thefollowing formula (IV-c):

wherein in the formula (IV-c), OBn represents benzyloxy, and (b)carrying out an intramolecular urea formation reaction.
 2. A process forpreparing a diazabicyclooctane compound represented by the followingformula (I):

wherein A represents RcO—; B represents NH or NC₁₋₆ alkyl; C representsSO₃M, wherein M represents H, an inorganic cation or an organic cation;Rc represents a C₁₋₆ alkyl group; A is substituted with one substituentFn1, wherein Fn1 represents an azetidine group, the process comprising:(a) removing the benzyl of the benzyloxy at the 6-position of a compoundrepresented by the following formula (IIa):

wherein in the formula (IIa), OBn represents a benzyloxy group, (b)preparing a compound of the following formula (IIb) in the presence of ahydrogenolysis catalyst and under a hydrogen atmosphere

and (c) sulfating the hydroxyl group at the 6-position of the formula(IIb) in the presence of a base, and optionally, deprotecting theprotective group in the side chain RcOB—.
 3. A process for preparing(2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamiderepresented by the following formula (III-059):

which comprises: among the compounds represented by the followingformulae (IV-a2), (IV-a3) and (IV-a4):

wherein in the formula (IV-a2), (IV-a3) or (IV-a4), TFA representstrifluoroacetyl, Boc represents tert-butoxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy, subjectingto coupling the compound represented by the formula (IV-a2) or (IV-a4)with tert-butyl 2-(aminooxy)ethylcarbamate in the presence of an activeester, an active amide or a dehydration condensing agent, or subjectingto coupling the compound represented by the formula (IV-a3) with benzyl2-(aminooxy)ethylcarbamate in the presence of an active ester, an activeamide or a dehydration condensing agent, to prepare a compoundrepresented by the following formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or(IV-b4-Boc-059):

wherein in the formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or(IV-b4-Boc-059), TFA represents trifluoroacetyl, Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy,deprotecting the trifluoroacetyl group of the compound represented bythe formula (IV-b2-Boc-059) by a treatment with a base to prepare acompound represented by the following formula (IV-c-Boc-059):

wherein in the formula (IV-c-Boc-059) or (IV-c-Cbz-059), Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents a benzyloxy, removing the tert-butoxycarbonyl of the compoundrepresented by the formula (IV-b3-Cbz-059) by an acid treatment toprepare a compound represented by the formula (IV-c-Cbz-059), orremoving the 2-trimethylsilylethoxycarbonyl of the compound representedby the formula (IV-b4-Boc-059) by a fluoride to prepare a compoundrepresented by the formula (IV-c-Boc-059), then, after silylating thecompound (IV-c-Boc-059) or (IV-c-Cbz-059), carrying out anintramolecular urea formation reaction to prepare a compound representedby the following formula (IIa-Boc-059) or (IIa-Cbz-059):

wherein in the above formula (IIa-Boc-059) or (IIa-Cbz-059), Bocrepresents tert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, andOBn represents benzyloxy, removing the benzyl of the benzyloxy at the6-position of the compound represented by the formula (IIa-Boc-059) inthe presence of a hydrogenolysis catalyst under a hydrogen atmosphere,or removing the benzyl of the benzyloxy at the 6-position of thecompound represented by the formula (IIa-Cbz-059) in the presence of ahydrogenolysis catalyst under a hydrogen atmosphere, and simultaneouslycarrying out a tert-butoxycarbonylation in the presence ofdi-tert-butoxydicarbonate to prepare a compound represented by thefollowing formula (IIb-Boc-059):

wherein in the formula (IIb-Boc-059), Boc representstert-butoxycarbonyl, sulfating the hydroxyl group at the 6-position ofthe formula (IIb-Buc-059) to prepare a compound represented by thefollowing formula (III-Boc-059):

wherein in the formula (III-Boc-059), Boc representstert-butoxycarbonyl, and M represents H, pyridinium, sodium ortetrabutylammonium, and deprotecting the tert-butoxycarbonyl group by anacid treatment.
 4. A process for preparing tert-butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate,or benzyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamaterepresented by the following formula (IIa-Boc-059) or (IIa-Cbz-059):

wherein in the formula (IIa-Boc-059) or (IIa-Cbz-059), Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, which comprises: among the compounds representedby the following formulae (IV-a2), (IV-a3) and (IV-a4):

wherein in the formula (IV-a2), (IV-a3) or (IV-a4), TFA representstrifluoroacetyl, Boc represents tert-butoxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy, subjectingto coupling each of the compounds represented by the formulae (IV-a2)and (IV-a4) in the presence of tert-butyl 2-(aminooxy)ethylcarbamate,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and1-hydroxybenzotriazolemonohydrate in combination, subjecting to couplingthe compounds represented by the formula (IV-a3) in the presence ofbenzyl 2-(aminooxy)ethylcarbamate,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and1-hydroxybenzotriazolemonohydrate in combination, to prepare a compoundrepresented by the following formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or(IV-b4-Boc-059):

wherein in the formula (IV-b2-Boc-059), (IV-b3-Cbz-059) or(IV-b4-Boc-059), TFA represents trifluoroacetyl, Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, Teoc represents2-trimethylsilylethoxycarbonyl, and OBn represents benzyloxy, removingthe trifluoroacetyl of the compound represented by the formula(IV-b2-Boc-059) in the presence of a base selected from the groupconsisting of lithium hydroxide, sodium hydroxide and potassiumhydroxide to prepare a compound represented by the following formula(IV-c-Boc-059):

wherein in the formula (IV-c-Boc-059) or (IV-c-Cbz-059), Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, removing the tert-butoxycarbonyl of the compoundrepresented by the formula (IV-b3-Cbz-059) in the presence of an acidselected from the group consisting of hydrochloric acid, sulfuric acid,methanesulfonic acid and trifluoroacetic acid to prepare a compoundrepresented by the formula (IV-c-Cbz-059), or removing the2-trimethylsilylethoxycarbonyl of the compound represented by theformula (IV-b4-Boc-059) in the presence of tetrabutylammonium fluorideto prepare a compound represented by the formula (IV-c-Boc-059), andsilylating the compound represented by the formula (IV-c-Boc-059) or(IV-c-Cbz-059) in the presence of chlorotrialkylsilane and subsequentlycarrying out an intramolecular urea formation reaction in the presenceof phosgene or diphosgene to prepare the compound represented by theformula (IIa-Boc-059) or (IIa-Cbz-059).
 5. A process for preparingtert-butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octo-2-yl]carbonyl}amino)oxy]ethyl}carbamate,or benzyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamaterepresented by the following formula (IIa-Boc-059) or (IIa-Cbz-059):

wherein in the formula (IIa-Boc-059) or (IIa-Cbz-059), Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, which comprises: silylating a compound representedby the following formula (IV-c-Boc-059) or (IV-c-Cbz-059):

wherein in the formula (IV-c-Boc-059) or (IV-c-Cbz-059), Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, in the presence of chlorotrimethylsilane, andsubsequently carrying out an intramolecular urea formation reaction inthe presence of phosgene or diphosgene.
 6. A process for preparing(2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamiderepresented by the following formula (III-059):

which comprises: among the compounds represented by the followingformulae (IIa-Boc-059) and (IIa-Cbz-059):

wherein in the formula (IIa-Boc-059) or (IIa-Cbz-059), Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, and OBnrepresents benzyloxy, removing the benzyl of the benzyloxy group at the6-position of the compound represented by the formula (IIa-Boc-059) inthe presence of palladium-carbon under a hydrogen atmosphere, orremoving the benzyl of the benzyloxy group at the 6-position of thecompound represented by the formula (IIa-Cbz-059) in the presence ofpalladium-carbon under a hydrogen atmosphere in the presence ofdi-tert-butoxydicarbonate, and simultaneously carrying out atert-butoxycarbonylation to prepare a compound represented by thefollowing formula (IIb-Boc-059):

wherein in the formula (IIb-Boc-059), Boc represents atert-butoxycarbonyl group, sulfating the hydroxyl group at the6-position of the formula (IIb-Boc-059) by a sulfur trioxide-pyridinecomplex in the presence of pyridine, 2-picoline or 2,6-lutidine, toprepare a compound represented by the following formula (III-Boc-059):

wherein in the formula (III-Boc-059), Boc representstert-butoxycarbonyl, and M represents H, pyridinium, sodium ortetrabutylammonium, and deprotecting the tert-butoxycarbonyl group by anacid selected from the group consisting of hydrochloric acid, sulfuricacid, methanesulfonic acid, trifluoroacetic acid and tetrafluoroboricacid.
 7. A process for preparing tert-butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octo-2-yl]carbonyl}amino)oxy]ethyl}carbamaterepresented by the following formula (IIa-Boc-059):

wherein in the formula (IIa-Boc-059), Boc representstert-butoxycarbonyl, Cbz represents benzyloxycarbonyl and OBn representsbenzyloxy, which comprises: silylating a compound represented by thefollowing formula (IV-c-Boc-059):

wherein in the formula (IV-c-Boc-059), Boc representstert-butoxycarbonyl and OBn represents benzyloxy, in the presence oftriethylamine and chlorotrimethylsilane, and subsequently carrying outan intramolecular urea formation reaction in the presence of phosgene ordiphosgene with a catalytic amount of 4-dimethylaminepyridine.
 8. Aprocess for preparing(2S,5R)—N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamiderepresented by the following formula (III-059):

which comprises: removing the benzyl of the benzyloxy at the 6-positionof a compound represented by the following formula (IIa-Boc-059):

wherein in the formula (IIa-Boc-059), Boc representstert-butoxycarbonyl, and OBn represents benzyloxy, in the presence ofpalladium-carbon under a hydrogen atmosphere to prepare a compoundrepresented by the following formula (IIb-Boc-059):

wherein in the formula (IIb-Boc-059), Boc representstert-butoxycarbonyl, sulfating the hydroxyl group at the 6-position ofthe formula (IIb-Boc-059) with a sulfur trioxide-pyridine complex in thepresence of pyridine, 2-picoline or 2,6-lutidine to prepare a compoundrepresented by the following formula (III-Boc-059):

wherein in the formula (III-Boc-059), Boc representstert-butoxycarbonyl, and M represents H, pyridinium, sodium ortetrabutylammonium, and deprotecting the tert-butoxycarbonyl group withan acid selected from the group consisting of hydrochloric acid,sulfuric acid, methanesulfonic acid, trifluoroacetic acid andtetrafluoroboric acid.
 9. A compound of a formula selected from thegroup consisting of

wherein in the above formulae, OMe represents a methoxy group and OBnrepresents a benzyloxy group.
 10. The compound of claim 9, which has theformula

wherein OBn represents a benzyloxy group.
 11. The compound of claim 9,which has the formula

wherein OBn represents a benzyloxy group.
 12. The compound of claim 9,which has the formula

wherein OBn represents a benzyloxy group and OMe represents a methoxygroup.
 13. The compound of claim 9, which has the formula

wherein OBn represents a benzyloxy group and OMe represents a methoxygroup.